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2.  Breast Cancer Subtype as a Predictor of Lymph Node Metastasis according to the SEER Registry 
Journal of Breast Cancer  2015;18(2):143-148.
Breast cancer subtype correlates with response to systemic therapy and overall survival (OS), but its impact on lymphatic spread is incompletely understood. In this study, we used the Surveillance, Epidemiology, and End Results registry to assess whether the subtype can predict the presence of nodal metastasis or advanced nodal stage in breast cancer.
A total of 7,274 eligible patients diagnosed with T1-3 infiltrating ductal carcinoma with known estrogen or progesterone hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, who underwent surgical excision of the primary tumor and pathologic lymph node evaluation, were included in this analysis. Patients were categorized into four breast cancer subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2+; and HR-/HER2-. Binary logistic regression analysis was used to determine whether breast cancer subtype, tumor size, tumor grade, patient race, and patient age at diagnosis are independently predictive of lymph node positivity or advanced nodal stage. The Pearson chi-square test was used to determine whether progesterone receptor (PR) status had an impact on the incidence of lymph node positivity in estrogen receptor (ER) positive patients.
Independent predictors of nodal positivity included breast cancer subtype (p=0.040), tumor size (p<0.001), tumor grade (p<0.001), and patient age (p<0.001), whereas only tumor size (p<0.001), grade (p=0.001), and patient age (p=0.005) predicted advanced nodal stage. Triple-negative cancers had a significantly lower risk of nodal positivity than the HR+/HER2- subtype (odds ratio, 0.686; p=0.004), but no other significant differences between subtypes were observed. There was also no difference in lymph node positivity between PR+ and PR- tumors amongst ER+/HER2- (p=0.228) or ER+/HER2+ tumors (p=0.713).
The HR+/HER2-breast cancer subtype has a higher rate of lymph node involvement at diagnosis than the triple-negative subtype. These findings may play a role in guiding regional management considerations if confirmed in further studies.
PMCID: PMC4490263  PMID: 26155290
Biological tumor markers; Breast neoplasms; Estrogen receptors
3.  The incidence of pelvic and para-aortic lymph node metastasis in uterine papillary serous and clear cell carcinoma according to the SEER registry 
In this study we utilized the Surveillance, Epidemiology and End-Results (SEER) registry to identify risk factors for lymphatic spread and determine the incidence of pelvic and para-aortic lymph node metastases in patients with uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) who underwent complete surgical staging and lymph node dissection.
Nine hundred seventy-two eligible patients diagnosed between 1998 to 2009 with International Federation of Gynecology and Obstetrics (FIGO) 1988 stage IA-IVA UPSC (n=685) or UCCC (n=287) were identified for analysis. Binomial logistic regression was used to determine risk factors for lymph node metastasis, with the incidence of pelvic and para-aortic lymph node metastases reported for each FIGO primary tumor stage. The Cox proportional hazards regression model was used to determine factors associated with overall survival.
FIGO primary tumor stage was the only independent risk factor for lymph node metastasis (p<0.01). The incidence of pelvis-only and para-aortic lymph node involvement according to the FIGO primary tumor stage were as follows: IA (2.3%/3.8%), IB (7.5%/5.2%), IC (22.5%/16.9%), IIA (20.8%/13.2%), IIB (25.7%/14.9%), and III/IV (25.7%/24.3%). Prognostic factors for overall survival included lymph node involvement (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.09 to 1.85; p<0.01), patient age >60 years (HR, 1.70; 95% CI, 1.21 to 2.41; p<0.01), and advanced FIGO primary tumor stage (p<0.01). Tumor grade, histologic subtype, and patient race did not predict for either lymph node metastasis or overall survival.
There is a high incidence of both pelvic and para-aortic lymph node metastases for FIGO stages IC and above uterine papillary serous and clear cell carcinomas, suggesting a potential role for lymph node-directed therapy for these patients.
PMCID: PMC4302280  PMID: 25310855
Adenocarcinoma Clear Cell; Lymphatic Metastasis; Registries; Risk Factors; Pelvis
4.  Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine 
The EPMA Journal  2014;5(1):16.
Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM.
PMCID: PMC4274760  PMID: 25538797
Personalized medicine; Hepatocellular carcinoma; Information technology; Model-guided therapy; Therapy imaging and model management system; TIMMS; Digital patient model; Patient-specific model; Model-based medical evidence; Bayesian network
5.  The Anatomical Biological Value on Pretreatment 18F-fluorodeoxyglucose Positron Emission Tomography Computed Tomography Predicts Response and Survival in Locally Advanced Head and Neck Cancer 
World Journal of Nuclear Medicine  2014;13(2):102-107.
18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) has become increasingly relevant in the staging of head and neck cancers, but its prognostic value is controversial. The objective of this study was to evaluate different PET/CT parameters for their ability to predict response to therapy and survival in patients treated for head and neck cancer. A total of 28 consecutive patients with a variety of newly diagnosed head and neck cancers underwent PET/CT scanning at our institution before initiating definitive radiation therapy. All underwent a posttreatment PET/CT to gauge tumor response. Pretreatment PET/CT parameters calculated include the standardized uptake value (SUV) and the anatomical biological value (ABV), which is the product of SUV and greatest tumor diameter. Maximum and mean values were studied for both SUV and ABV, and correlated with response rate and survival. The mean pretreatment tumor ABVmax decreased from 35.5 to 7.9 (P = 0.0001). Of the parameters tested, only pretreatment ABVmax was significantly different among those patients with a complete response (CR) and incomplete response (22.8 vs. 65, respectively, P = 0.021). This difference was maximized at a cut-off ABVmax of 30 and those patients with ABVmax < 30 were significantly more likely to have a CR compared to those with ABVmax of ≥ 30 (93.8% vs. 50%, respectively, P = 0.023). The 5-year overall survival was 80% compared to 36%, respectively, (P = 0.028). Multivariate analysis confirmed that ABVmax was an independent prognostic factor. Our data supports the use of PET/CT, and specifically ABVmax, as a prognostic factor in head and neck cancer. Patients who have an ABVmax ≥ 30 were more likely to have a poor outcome with chemoradiation alone, and a more aggressive trimodality approach may be indicated in these patients.
PMCID: PMC4150151  PMID: 25191124
18F-fluorodeoxyglucose; head and neck cancer; positron emission tomography/computed tomography
6.  A predictive model to guide management of the overlap region between target volume and organs at risk in prostate cancer volumetric modulated arc therapy 
Radiation Oncology Journal  2014;32(1):23-30.
The goal of this study is to determine whether the magnitude of overlap between planning target volume (PTV) and rectum (Rectumoverlap) or PTV and bladder (Bladderoverlap) in prostate cancer volumetric-modulated arc therapy (VMAT) is predictive of the dose-volume relationships achieved after optimization, and to identify predictive equations and cutoff values using these overlap volumes beyond which the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose-volume constraints are unlikely to be met.
Materials and Methods
Fifty-seven patients with prostate cancer underwent VMAT planning using identical optimization conditions and normalization. The PTV (for the 50.4 Gy primary plan and 30.6 Gy boost plan) included 5 to 10 mm margins around the prostate and seminal vesicles. Pearson correlations, linear regression analyses, and receiver operating characteristic (ROC) curves were used to correlate the percentage overlap with dose-volume parameters.
The percentage Rectumoverlap and Bladderoverlap correlated with sparing of that organ but minimally impacted other dose-volume parameters, predicted the primary plan rectum V45 and bladder V50 with R2 = 0.78 and R2 = 0.83, respectively, and predicted the boost plan rectum V30 and bladder V30 with R2 = 0.53 and R2 = 0.81, respectively. The optimal cutoff value of boost Rectumoverlap to predict rectum V75 >15% was 3.5% (sensitivity 100%, specificity 94%, p < 0.01), and the optimal cutoff value of boost Bladderoverlap to predict bladder V80 >10% was 5.0% (sensitivity 83%, specificity 100%, p < 0.01).
The degree of overlap between PTV and bladder or rectum can be used to accurately guide physicians on the use of interventions to limit the extent of the overlap region prior to optimization.
PMCID: PMC3977128  PMID: 24724048
Prostate cancers; Organs at risk; Radiation injuries; Computer assisted radiotherapy planning; Intensity-modulated radiotherapy
8.  Comparison study of intensity modulated arc therapy using single or multiple arcs to intensity modulated radiation therapy for high-risk prostate cancer 
Radiation Oncology Journal  2013;31(2):104-110.
Intensity modulated arc therapy (IMAT) is a form of intensity modulated radiation therapy (IMRT) that delivers dose in single or multiple arcs. We compared IMRT plans versus single-arc field (1ARC) and multi-arc fields (3ARC) IMAT plans in high-risk prostate cancer.
Materials and Methods
Sixteen patients were studied. Prostate (PTVP), right pelvic (PTVRtLN) and left pelvic lymph nodes (PTVLtLN), and organs at risk were contoured. PTVP, PTVRtLN, and PTVLtLN received 50.40 Gy followed by a boost to PTVB of 28.80 Gy. Three plans were per patient generated: IMRT, 1ARC, and 3ARC. We recorded the dose to the PTV, the mean dose (DMEAN) to the organs at risk, and volume covered by the 50% isodose. Efficiency was evaluated by monitor units (MU) and beam on time (BOT). Conformity index (CI), Paddick gradient index, and homogeneity index (HI) were also calculated.
Average Radiation Therapy Oncology Group CI was 1.17, 1.20, and 1.15 for IMRT, 1ARC, and 3ARC, respectively. The plans' HI were within 1% of each other. The DMEAN of bladder was within 2% of each other. The rectum DMEAN in IMRT plans was 10% lower dose than the arc plans (p < 0.0001). The GI of the 3ARC was superior to IMRT by 27.4% (p = 0.006). The average MU was highest in the IMRT plans (1686) versus 1ARC (575) versus 3ARC (1079). The average BOT was 6 minutes for IMRT compared to 1.3 and 2.9 for 1ARC and 3ARC IMAT (p < 0.05).
For high-risk prostate cancer, IMAT may offer a favorable dose gradient profile, conformity, MU and BOT compared to IMRT.
PMCID: PMC3712173  PMID: 23865007
High risk prostate cancer; Intensity modulated arc therapy; Intensity modulated radiation therapy; RapidArc
9.  The role of PET/CT in decreasing inter-observer variability in treatment planning and evaluation of response for cervical cancer 
We have previously introduced anatomic biologic contouring (ABC) with PET/CT, using a distinct “halo” to unify contouring methods in treatment planning for lung and head and neck cancers. The objective of this study is to assess the utility of PET/CT in planning and treatment response for cervical cancer. Forty-two patients with stages II-IIIB cervix cancer were planned for irradiation using PET/CT. A CT-based Gross Tumor Volume (GTV-CT) was delineated by two independent observers while the PET remained obscured. The Planning Target Volume (PTV) was obtained by adding a 1.5 cm margin around the GTV. The same volumes were recontoured using PET/CT data and termed GTV-ABC and PTV-ABC, respectively. The values of GTV-CT and GTV-ABC and the absolute differences between the two observers were analyzed. Additionally, 23 of these patients had PET/CT performed 3 months after treatment. The anatomic biologic value (ABV) was calculated using the product of maximum diameter and mean SUV of the cervical tumor. The pre- and post-treatment ABVs were compared. A “halo” was observed around areas of maximal SUV uptake. The mean halo SUV was 1.91 ± 0.56 (SD). The mean halo thickness was 2.12 ± 0.5 (SD) mm. Inter-observer GTV variability decreased from a mean volume difference of 55.36 cm3 in CT-based planning to 12.29 cm3 in PET/CT-based planning with a respective decrease in standard deviation (SD) from 55.78 to 10.24 (p <0.001). Comparison of mean pre-treatment and post-treatment ABV’s revealed a decrease of ABV from 48.2 to 7.8 (p<0.001). PET/CT is a valuable tool in radiation therapy planning and evaluation of treatment response for cervical cancer. A clearly visualized “halo” was successfully implemented in GTV contouring in cervical cancer, resulting in decreased inter-observer variability in planning. PET/CT has the ability to quantify treatment response using anatomic biologic value.
PMCID: PMC3477735  PMID: 23133818
Cervical cancer; positron emission tomography; PET/CT; treatment planning; inter-observer variability
10.  Case series analysis of post-brachytherapy prostate edema and its relevance to post-implant dosimetry. Post-implant prostate edema and dosimetry 
We evaluated the post-operative pattern of prostate volume (PV) changes following prostate brachytherapy (PB) and analyzed variables which affect swelling.
Material and methods
Twenty-nine patients treated with brachytherapy (14) or combined brachytherapy and external beam radiotherapy modality (15) underwent pre- and post-implant computed tomography (CT). Prostate volume measurements were done on post-operative days 1, 9, 30, and 60. An observer performed 139 prostate volume (PV) measurements. We analyzed the influence of pre-implant PV, number of needles and insertion attempts, number and activity of seeds, Gleason score, use of hormonal therapy and external beam radiation therapy on the extent of edema. We computed a volume correction factor (CF) to account for dosimetric changes between day 1 and day 30. Using the calculated CF, the dose received by 90% (D90) of the prostate on day 30 (D90Day30) was obtained by dividing day 1 (D90Day1) by the CF.
The mean PV recorded on post-operative day 1 was 67.7 cm3, 18.8 cm3 greater than average pre-op value (SD 15.6 cm3). Swelling returned to pre-implant volume by day 30. Seed activity, treatment modality, and Gleason score were significant variables. The calculated CF was 0.76. After assessment using the CF, the mean difference between estimated and actual D90Day30 was not significant.
We observed maximum prostate size on post-operative day 1, returning to pre-implant volume by day 30. This suggests that post-implant dosimetry should be obtained on or after post-operative day 30. If necessary, day 30 dosimetry can be estimated by dividing D90Day1 by a correction factor of 0.76.
PMCID: PMC3552628  PMID: 23349648
prostate brachytherapy; post-implant dosimetry; computed brachytherapy

Results 1-10 (10)