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Marita Morgia,
Julie Cuartero,
Lorraine Walsh,
John Jezioranski,
Kirsten Keeler,
Jason Xie,
Christine Massey,
Debbie Williamson,
Young-Bin Cho,
Seungjong Oh,
Anthony Fyles, Michael Milosevic
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ABSTRACT: BACKGROUND AND PURPOSE: To analyze systematic changes in tumor and normal tissue anatomy and dosimetry using serial MR imaging during pulsed dose rate brachytherapy (PDR BT) for cervical cancer. MATERIAL AND METHODS: Forty-three patients with cervical cancer underwent MR-guided PDR BT using an intrauterine applicator alone after external beam radiotherapy. MR imaging was repeated on days 2 and 3 of treatment and the day 1 plan was applied to the re-contoured volumes. RESULTS: The mean uterine volume and mean HR CTV increased during treatment. This resulted in a decrease in the mean HR CTV D90 relative to the day 1 planned dose. There was no change in the mean bladder volume during treatment but the mean rectal volume increased. This correlated with an increase in the mean rectal dose. There were four local recurrences. There was no apparent relationship between either the planned or the delivered HR CTV D90 and local recurrence. There was only one case of late bladder toxicity but nine patients developed late rectal toxicity. The cumulative rectal dose during treatment was a better predictor of late rectal toxicity than the planned dose. CONCLUSIONS: Significant changes in tumor and normal tissue anatomy and dosimetry can occur during PDR BT and should be tracked and corrected using serial imaging and plan adaptation, especially when the day 1 tumor or normal tissue doses are close to the planning constraints.
Radiotherapy and Oncology 03/2013; · 5.58 Impact Factor
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ABSTRACT: This work is to compare the kinetic parameters derived from the DCE-CT and -MR data of a group of 37 patients with cervical cancer. The modified Tofts model and the reference tissue method were applied to estimate kinetic parameters. In the MR kinetic analyses using the modified Tofts model for each patient data set, both the arterial input function (AIF) measured from DCE-MR images and a population-averaged AIF from the literature were applied to the analyses, while the measured AIF was used for the CT kinetic analysis. The kinetic parameters obtained from both modalities were compared. Significant moderate correlations were found in modified Tofts parameters [volume transfer constant(K(trans) ) and rate constant (k(ep) )] between CT and MR analysis for MR with the measured AIFs (R = 0·45, P<0·01 and R = 0·40, P<0·01 in high-K(trans) region; R = 0·38, P<0·01 and R = 0·80, P<0·01 in low-K(trans) region) as well as with the population-averaged AIF (R = 0·59, P<0·01 and R = 0·62, P<0·01 in high-K(trans) region; R = 0·50, P<0·01 and R = 0·63, P<0·01 in low-K(trans) region), respectively. In addition, from the Bland-Altman plot analysis, it was found that the systematic biases (the mean difference) between the modalities were drastically reduced in magnitude by adopting the population-averaged AIF for the MR analysis instead of the measured ones (from 51·5% to 18·9% for K(trans) and from 21·7% to 4·1% for k(ep) in high-K(trans) region; from 73·0% to 29·4% for K(trans) and from 63·4% to 24·5% for k(ep) in low-K(trans) region). The preliminary results showed the feasibility in the interchangeable use of the two imaging modalities in assessing cervical cancers.
Clinical Physiology and Functional Imaging 03/2013; 33(2):150-61. · 1.33 Impact Factor
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Warren D Foltz,
Andy Wu,
Peter Chung,
Charles Catton,
Andrew Bayley, Michael Milosevic,
Robert Bristow,
Padraig Warde,
Anna Simeonov,
David A Jaffray,
Masoom A Haider,
Cynthia Ménard
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ABSTRACT: PURPOSE: To evaluate regional and temporal changes in apparent diffusion coefficient (ADC) and T(2) relaxation during radiation therapy (RT) in patients with low and intermediate risk localized prostate cancer. MATERIALS AND METHODS: Seventeen patients enrolled on a prospective clinical trial where MRI was acquired every 2 weeks throughout eight weeks of image-guided prostate IMRT (78 Gy/39 fractions). ADC and T(2) quantification used entire prostate, central gland, benign peripheral zone, and tumor-dense regions-of-interest, and mean values were evaluated for common response trends. RESULTS: Overall, the RT responses were greater than volunteer measurement repeatability, and week 6 appeared to be an optimum time-point for early detection. RT effects on the entire prostate were best detected using ADC (5-7% by week 2, P < 0.0125), effects on peripheral zone were best detected using T(2) (19% reduction at week 6; P = 0.004) and effects on tumors were best detected using ADC (14% elevation at week 6; P = 0.004). CONCLUSION: ADC and T(2) may be candidate biomarkers of early response to RT warranting further investigation against clinical outcomes. J. Magn. Reson. Imaging 2012;. © 2012 Wiley Periodicals, Inc.
Journal of Magnetic Resonance Imaging 10/2012; · 2.70 Impact Factor
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Chad M McKee,
Danmei Xu,
Yunhong Cao,
Sheheryar Kabraji,
Danny Allen,
Veerle Kersemans,
John Beech,
Sean Smart,
Freddie Hamdy,
Adrian Ishkanian, [......],
Melania Pintile, Michael Milosevic,
Theodorus van der Kwast,
Gaetano Zafarana,
Varune Rohan Ramnarine,
Igor Jurisica,
Chad Mallof,
Wan Lam,
Robert G Bristow,
Ruth J Muschel
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ABSTRACT: Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
The Journal of clinical investigation 10/2012; · 15.39 Impact Factor
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Corinne M Doll,
Christina Aquino-Parsons,
Melania Pintilie,
Alexander C Klimowicz,
Stephanie K Petrillo, Michael Milosevic,
Peter S Craighead,
Blaise Clarke,
Susan P Lees-Miller,
Anthony W Fyles,
Anthony M Magliocco
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ABSTRACT: 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.
International journal of radiation oncology, biology, physics 07/2012; · 4.59 Impact Factor
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Michael Milosevic,
Padraig Warde,
Cynthia Ménard,
Peter Chung,
Ants Toi,
Adrian Ishkanian,
Michael McLean,
Melania Pintilie,
Jenna Sykes,
Mary Gospodarowicz,
Charles Catton,
Richard P Hill,
Robert Bristow
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ABSTRACT: Tumor hypoxia is an important determinant of outcome in many human malignancies and is associated with treatment resistance and metastases. The aim of this study was to determine the effect of hypoxia in patients with prostate cancer treated with radiotherapy.
Tumor hypoxia was measured in 247 patients with clinically localized prostate cancer before radiotherapy, with or without hormonal therapy. The median pO(2) was 6.8 mm Hg and the median hypoxic percentage less than 10 mm Hg (HP(10)) was 63%. The median follow-up was 6.6 years.
The 5-year biochemical relapse-free rate (bRFR) was 78%. Prostrate-specific antigen and Gleason score were both associated with biochemical relapse and formed a baseline clinical model. The effect of hypoxia was found to vary with the duration of patient follow-up. HP(10), when added to the clinical model, was an independent predictor of early bRFR (P = 0.019). The relationship between hypoxia and early bRFR was more pronounced when the analysis was restricted to 142 patients with bulk tumor at the site of the oxygen measurements (P = 0.004). Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during follow-up (P = 0.043), again with the effect being greatest early after completing treatment.
This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It shows that hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland.
Clinical Cancer Research 04/2012; 18(7):2108-14. · 7.74 Impact Factor
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International journal of radiation oncology, biology, physics 03/2012; 82(4):1319. · 4.59 Impact Factor
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Yi Wang,
Olga Roche,
Chaoying Xu,
Eduardo H Moriyama,
Pardeep Heir,
Jacky Chung,
Frederik C Roos,
Yonghong Chen,
Greg Finak, Michael Milosevic,
Brian C Wilson,
Bin Tean Teh,
Morag Park,
Meredith S Irwin,
Michael Ohh
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ABSTRACT: Caveolin-1 (CAV1) is an essential structural constituent of caveolae, specialized lipid raft microdomains on the cell membrane involved in endocytosis and signal transduction, which are inexplicably deregulated and are associated with aggressiveness in numerous cancers. Here we identify CAV1 as a direct transcriptional target of oxygen-labile hypoxia-inducible factor 1 and 2 that accentuates the formation of caveolae, leading to increased dimerization of EGF receptor within the confined surface area of caveolae and its subsequent phosphorylation in the absence of ligand. Hypoxia-inducible factor-dependent up-regulation of CAV1 enhanced the oncogenic potential of tumor cells by increasing the cell proliferative, migratory, and invasive capacities. These results support a concept in which a crisis in oxygen availability or a tumor exhibiting hypoxic signature triggers caveolae formation that bypasses the requirement for ligand engagement to initiate receptor activation and the critical downstream adaptive signaling during a period when ligands required to activate these receptors are limited or are not yet available.
Proceedings of the National Academy of Sciences 03/2012; 109(13):4892-7. · 9.68 Impact Factor
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Supriya Chopra,
Ants Toi,
Nathan Taback,
Andrew Evans,
Masoom A Haider, Michael Milosevic,
Robert G Bristow,
Peter Chung,
Andrew Bayley,
Gerard Morton,
Danny Vesprini,
Padraig Warde,
Charles Catton,
Cynthia Ménard
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ABSTRACT: Rational design of targeted radiotherapy (RT) in prostate cancer (Pca) hinges on a better understanding of spatial patterns of recurrence. We sought to identify pathological factors predictive for site of local recurrence (LR) after external beam RT.
Prospective databases were reviewed to identify men with LR after RT from 1997 through 2009. Patients with biochemical failure and biopsy-confirmed Pca more than 2 years after RT were evaluated. Prediction for site of recurrence based on the following pretreatment factors was determined on independent and cluster-sextant basis: presence of malignancy, dominant vs. nondominant percentage core length (PCL) involvement, PCL ≥ or <40%, and Gleason score. Sites of dominant PCL were defined as sextants with peak PCL involvement minus 10%, and >5% for each patient.
Forty-one patients with low-intermediate risk Pca constituted the study cohort. Median time to biopsy after RT was 51 months (range, 24-145). Of 246 sextants, 74 were involved with tumor at baseline. When sextants are treated as independent observations the presence of malignancy (77% vs. 22%, p = 0.0001), dominant PCL (90% vs. 46%, p = 0.0001), and PCL ≥40% (89% vs. 68 %, p = 0.04) were found to be significant predictors for LR, although PCL ≥40% did not retain statistical significance if sextants were considered correlated. The vast majority of patients (95%) recurred at the original site of dominant PCL or PCL ≥40%, and 44% also recurred in regions of nondominant PCL <40% (n = 8) and/or benign sampling (n = 14) at baseline.
LR after RT predominantly occurs in regions bearing higher histological tumor burden but are not isolated to these sites. Our data highlights the value of spatially resolved baseline pathological sampling and may assist in the design of clinical trials tailoring RT dose prescriptions to subregions of the prostate gland.
International journal of radiation oncology, biology, physics 03/2012; 82(3):e441-8. · 4.59 Impact Factor
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ABSTRACT: The specialty of radiation oncology has experienced significant workforce planning challenges in many countries. Our purpose was to develop and validate a workforce-planning model that would forecast the balance between supply of, and demand for, radiation oncologists in Canada over a minimum 10-year time frame, to identify the model parameters that most influenced this balance, and to suggest how this model may be applicable to other countries.
A forward calculation model was created and populated with data obtained from national sources. Validation was confirmed using a historical prospective approach.
Under baseline assumptions, the model predicts a short-term surplus of RO trainees followed by a projected deficit in 2020. Sensitivity analyses showed that access to radiotherapy (proportion of incident cases referred), individual RO workload, average age of retirement and resident training intake most influenced balance of supply and demand. Within plausible ranges of these parameters, substantial shortages or excess of graduates is possible, underscoring the need for ongoing monitoring.
Workforce planning in radiation oncology is possible using a projection calculation model based on current system characteristics and modifiable parameters that influence projections. The workload projections should inform policy decision making regarding growth of the specialty and training program resident intake required to meet oncology health services needs. The methods used are applicable to workforce planning for radiation oncology in other countries and for other comparable medical specialties.
Radiotherapy and Oncology 01/2012; 103(1):123-9. · 5.58 Impact Factor
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Gaetano Zafarana,
Adrian S Ishkanian,
Chad A Malloff,
Jennifer A Locke,
Jenna Sykes,
John Thoms,
Wan L Lam,
Jeremy A Squire,
Maisa Yoshimoto,
Varune Rohan Ramnarine,
Alice Meng,
Omar Ahmed,
Igor Jurisca, Michael Milosevic,
Melania Pintilie,
Theo van der Kwast,
Robert G Bristow
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ABSTRACT: Despite the use of PSA, Gleason score, and T-category as prognosticators in intermediate-risk prostate cancer, 20-40% of patients will fail local therapy. In order to optimize treatment approaches for intermediate-risk patients, additional genetic prognosticators are needed. Previous reports using array comparative genomic hybridization (aCGH) in radical prostatectomy cohorts suggested a combination of allelic loss of the PTEN gene on 10q and allelic gain of the c-MYC gene on 8q were associated with metastatic disease. We tested whether copy number alterations (CNAs) in PTEN (allelic loss) and c-MYC (allelic gain) were associated with biochemical relapse following modern-era, image-guided radiotherapy (mean dose 76.4 Gy). We used aCGH analyses validated by fluorescence in-situ hybridization (FISH) of DNA was derived from frozen, pre-treatment biopsies in 126 intermediate-risk prostate cancer patients. Patients whose tumors had CNAs in both PTEN and c-MYC had significantly increased genetic instability (percent genome alteration; PGA) compared to tumors with normal PTEN and c-MYC status (p < 0.0001). We demonstrate that c-MYC gain alone, or combined c-MYC gain and PTEN loss, were increasingly prognostic for relapse on multivariable analyses (hazard ratios (HR) of 2.58/p = 0.005 and 3.21/p = 0.0004; respectively). Triaging patients by the use of CNAs within pre-treatment biopsies may allow for better use of systemic therapies to target sub-clinical metastases or locally recurrent disease and improve clinical outcomes.
Cancer 01/2012; 118(16):4053-62. · 4.77 Impact Factor
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ABSTRACT: Tumor oxygenation status is considered one of the important prognostic markers in cancer since it strongly influences the response of cancer cells to various treatments; in particular, to radiation therapy. Thus, a proper and accurate assessment of tumor oxygen distribution before the treatment may highly affect the outcome of the treatment. The heterogeneous nature of tumor hypoxia, mainly influenced by the complex tumor microenvironment, often makes its quantification very difficult. The usual methods used to measure tumor hypoxia are biomarkers and the polarographic needle electrode. Although these techniques may provide an acceptable assessment of hypoxia, they are invasive and may not always give a spatial distribution of hypoxia, which is very useful for treatment planning. An alternative method to quantify the tumor hypoxia is to use theoretical simulations with the knowledge of tumor vasculature. The purpose of this paper is to model tumor hypoxia using a known spatial distribution of tumor vasculature obtained from image data, to analyze the accuracy of polarographic needle electrode measurements in quantifying hypoxia, to quantify the optimum number of measurements required to satisfactorily evaluate the tumor oxygenation status, and to study the effects of hypoxia on radiation response. Our results indicate that the model successfully generated an accurate oxygenation map for tumor cross-sections with known vascular distribution. The method developed here provides a way to estimate tumor hypoxia and provides guidance in planning accurate and effective therapeutic strategies and invasive estimation techniques. Our results agree with the previous findings that the needle electrode technique gives a good estimate of tumor hypoxia if the sampling is done in a uniform way with 5-6 tracks of 20-30 measurements each. Moreover, the analysis indicates that the accurate measurement of oxygen profile can be very useful in determining right radiation doses to the patients.
Computational and Mathematical Methods in Medicine 01/2012; 2012:410602. · 0.68 Impact Factor
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Jennifer A Locke,
Gaetano Zafarana,
Chad A Malloff,
Wan L Lam,
Jenna Sykes,
Melania Pintilie,
Varune Rohan Ramnarine,
Alice Meng,
Omer Ahmed,
Igor Jurisica,
Emma Tomlinson Guns,
Theo van der Kwast, Michael Milosevic,
Robert G Bristow
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ABSTRACT: Androgen deprivation therapy (ADT) and novel agents targeting the androgen synthesis axis (e.g., abiraterone acetate) are adjuvant therapies that are currently, or may in the future be, combined with radiotherapy to reduce the chance of disease relapse. Little is known about allelic loss or gain pertaining to genes associated with the androgen synthesis axis and whether this is prognostic in patients who receive localized radiotherapy. In this hypothesis generating study, we conducted an array comparative genomic hybridization (aCGH) analysis of 33 androgen synthesis genes to identify potential prognostic factors for radiotherapy outcome.
aCGH analysis of tumor DNA prospectively derived from frozen needle biopsies of 126 men with intermediate-risk disease who underwent image-guided radiotherapy (IGRT) to a mean dose of 76.4 Gy was conducted. Statistical analyses were conducted for allelic loss or gain in genes as potential prognostic factors relative to prostate specific antigen, Gleason-score, and T-category.
We observed that allelic losses of loci containing the genes StAR and HSD17B2 were associated with increased genetic instability (as determined by percentage genome alteration). On multivariate analyses these loci were prognostic for biochemical disease-free relapse (StAR: HR = 2.84, 95% CI: 1.44-5.61, P = 0.00269; HSD17B2: HR = 1.97, 95% CI: 1.06-3.64, P = 0.031). The results were validated in a surgical cohort of 131 intermediate-risk patients.
Allelic losses of the loci containing StAR and HSD17B2 have significant prognostic value for intermediate-risk prostate cancer. With this hypothesis generating information future studies should test StAR and HSD17B2 losses as biomarkers of androgen response in combined modality protocols.
The Prostate 12/2011; 72(12):1295-305. · 3.48 Impact Factor
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Danny Vesprini,
Charles Catton,
Lindsay Jacks,
Gina Lockwood,
Tara Rosewall,
Andrew Bayley,
Peter Chung,
Mary Gospodarowicz,
Cynthia Ménard, Michael Milosevic,
Alan Nichol,
Marketa Skala,
Padraig Warde,
Robert G Bristow
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ABSTRACT: Prostate cancer patients exhibit variability in normal tissue reactions and biochemical failure. With the use of image-guided radiotherapy (IGRT), there is a greater likelihood that the differences in normal tissue and tumor response are due to biological rather than physical factors. We tested the hypothesis that prospectively scored acute toxicity is associated with biochemical failure-free rate (BFFR) in prostate cancer patients treated with IGRT.
We retrospectively analyzed BFFR in 362 patients with localized prostate cancer treated with IGRT. We compared BFFR with prospectively collected Radiation Therapy Oncology Group (RTOG) maximum acute gastrointestinal (GI) and genitourinary (GU) toxicity scores. Median follow-up for all patients was 58.3 months after total radiotherapy doses of 75.6-79.8 Gy.
Patients reporting RTOG acute GU or GI toxicity scores of ≥ 2 were considered "sensitive" (n = 141, 39%) and patients reporting scores <2 were considered "nonsensitive" (n = 221, 61%). When calculating biochemical failure (BF) using the American Society for Therapeutic Radiology and Oncology definition at 5 years, 76% (CI 70-82%) of the "nonsensitive" patients were failure free, compared with only 53% (CI 43-62%) of the "sensitive" patients (log-rank test, p < 0.0001). This difference was also observed using the Phoenix definition; "nonsensitive" 5-year BFFR was 81% (CI 74-86%) vs. "sensitive" BFFR was 68% (CI 58-76%; log-rank test p = 0.0012). The difference in BF between cohorts remained significant when controlled for radiation dose (75.6 vs. 79.8 Gy), prognostic stratification (T category, prostate-specific antigen, and Gleason score), and prostate volume.
This study unexpectedly shows that prostate cancer patients who develop ≥ Grade 2 RTOG acute toxicity during radiotherapy are less likely to remain BFF at 5 years. These results deserve further study and, if validated in other large IGRT cohorts, additional models would be required to study interaction between normal tissue and tumor biology in prostate cancer patients.
International journal of radiation oncology, biology, physics 11/2011; 83(2):608-16. · 4.59 Impact Factor
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Jennifer A Locke,
Gaetano Zafarana,
Adrian S Ishkanian, Michael Milosevic,
John Thoms,
Cherry L Have,
Chad A Malloff,
Wan L Lam,
Jeremy A Squire,
Melania Pintilie,
Jenna Sykes,
Varune Rohan Ramnarine,
Alice Meng,
Omer Ahmed,
Igor Jurisica,
Theo van der Kwast,
Robert G Bristow
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ABSTRACT: Despite the use of prostate specific antigen (PSA), Gleason-score, and T-category as prognostic factors, up to 40% of patients with intermediate-risk prostate cancer will fail radical prostatectomy or precision image-guided radiotherapy (IGRT). Additional genetic prognosticators are needed to triage these patients toward intensified combination therapy with novel targeted therapeutics. We tested the role of the NKX3.1 gene as a determinant of treatment outcome given its reported roles in tumor initiating cell (TIC) renewal, the DNA damage response, and cooperation with c-MYC during prostate cancer progression.
Using high-resolution array comparative genomic hybridization (aCGH), we profiled the copy number alterations in TIC genes using tumor DNA from frozen needle biopsies derived from 126 intermediate-risk patients who underwent IGRT. These data were correlated to biochemical relapse-free rate (bRFR) by the Kaplan-Meier method and Cox proportional hazards models.
A screen of the aCGH-IGRT data for TIC genes showed frequent copy number alterations for NKX3.1, PSCA, and c-MYC. NKX3.1 haploinsufficiency was associated with increased genomic instability independent of PSA, T-category, and Gleason-score. After adjusting for clinical factors in a multivariate model, NKX3.1 haploinsufficiency was associated with bRFR when tested alone (HR = 3.05, 95% CI: 1.46-6.39, P = 0.0030) or when combined with c-MYC gain (HR = 3.88, 95% CI: 1.78-8.49, P = 0.00067). A similar association was observed for patients following radical prostatectomy with a public aCGH database. NKX3.1 status was associated with positive biopsies post-IGRT and increased clonogen radioresistance in vitro.
Our results support the use of genomic predictors, such as NKX3.1 status, in needle biopsies for personalized approaches to prostate cancer management.
Clinical Cancer Research 11/2011; 18(1):308-16. · 7.74 Impact Factor
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ABSTRACT: 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).
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.
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).
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.
Cancer 10/2011; 118(12):3105-15. · 4.77 Impact Factor
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ABSTRACT: In dynamic contrast enhanced CT (DCE-CT) study, prolonged CT scanning with high temporal resolution is required to give accurate and precise estimates of kinetic parameters. However, such scanning protocol could lead to substantial radiation dose to the patient. A novel method is proposed to reduce radiation dose to patient, while maintaining high accuracy for kinetic parameter estimates in DCE-CT study.
The method is based on a previous investigation that the arterial impulse response (AIR) in DCE-CT study can be predicted using a population-based scheme. In the proposed method, DCE-CT scanning is performed with relatively low temporal resolution, hence, giving rise to reduction in patient dose. A novel method is proposed to estimate the arterial input function (AIF) based on the coarsely sampled AIF. By using the estimated AIF in the tracer kinetic analysis of the coarsely sampled DCE-CT study, the calculated kinetic parameters are able to achieve a high degree of accuracy. The method was tested on a DCE-CT data set of 48 patients with cervical cancer scanned at high temporal resolution. A random cohort of 34 patients was chosen to construct the orthonormal bases of the AIRs via singular value decomposition method. The determined set of orthonormal bases was used to fit the AIFs in the second cohort (14 patients) at varying levels of down sampling. For each dataset in the second cohort, the estimated AIF was used for kinetic analyses of the modified Tofts and adiabatic tissue homogeneity models for each of the down-sampling schemes between intervals from 2 to 15 s. The results were compared with analyses done with the "raw" down-sampled AIF.
In the first group of 34 patients, there were 11 orthonormal bases identified to describe the AIRs. The AIFs in the second group were estimated in high accuracy based on the 11 orthonormal bases established in the first group along with down-sampled AIFs. Using the 11 orthonormal bases, the estimated AIFs for the second group were found to have an averaged maximal percentage error of 3.4% ± 7.5% in all sampling schemes up to 15 s. The results of kinetic analysis with the proposed method compared with down sampling alone showed that the proposed method is superior in maintaining the accuracy in volume transfer constant (K(trans) ) after 9 s down-sampling interval, blood volume (v(b) ) for almost all down-sampling intervals, and blood flow (F) after 11 s down-sampling interval. The preliminary results suggested that the proposed method is able to support scanning intervals of 10-15 s at a cost of 6.2%-10.0% loss in accuracy of K(trans) and 10.9%-19.4% in v(b), and the scanning intervals of 12-15 s at a cost of 9.7%-14.6% for F in DEC-CT studies for patients with cervix cancer.
The proposed method of AIF estimation allows low scanning frequency in DCE-CT study to reduce radiation dose to patient, while maintaining relatively high accuracy in the kinetic parameter estimates. The initial results suggested that the method is applicable for DCE-CT studies for patients with cervical cancer.
Medical Physics 09/2011; 38(9):5094-103. · 2.83 Impact Factor
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ABSTRACT: To discuss the important technological advances that have taken place in the planning and delivery of both external beam radiotherapy and brachytherapy for patients with locally advanced cervical cancer, and the implications for improved clinical outcomes.
Technological advances in external beam radiation treatment and brachytherapy for patients with cervical cancer allow more precise targeting of tumour and relative sparing of surrounding normal organs and tissues. Early evidence is emerging to indicate that these advances will translate into improvements in tumour control and reduced side effects. However, there are patient, tumour and treatment-related factors that can detract from these benefits. Foremost among these is complex, unpredictable and sometimes dramatic internal tumour and normal organ motion during treatment. The focus of current research and clinical development is on tracking internal anatomic change in individual patients and adapting treatment plans as required to assure that optimal tumour coverage and normal tissue sparing is maintained at all times. The success of this approach will depend on clear definitions of target volumes, high resolution daily soft tissue imaging, and new software tools for rapid contouring, treatment planning and quality assurance.
Radiation treatment of locally advanced cervical cancer is evolving rapidly, driven by advances in technology, towards more individualized patient care that has the potential to substantially improve clinical outcomes.
Current opinion in oncology 09/2011; 23(5):512-8. · 4.09 Impact Factor
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ABSTRACT: To quantify the effect of delineation method on bladder DVH, observer variability (OV) and contouring time for prostate IMRT plans.
Planning CT scans and IMRT plans of 30 prostate cancer patients were anonymized. For 20 patients, 1 observer delineated the bladder using 9 methods. The effect of delineation method on the DVH curve, discrete dose levels and delineation time was quantified. For the 10 remaining CTs, 6 observers delineated bladder wall using 4 methods. Observer-based volume variation and intraclass correlation coefficient (ICC) were used to describe the dosimetric effects of OV.
Manual delineation of the bladder wall (BW_m) was significantly slower than any other method (mean: 20 min vs. ≤ 13 min) and the dosimetric effect of OV was significantly larger (V70 Gy ICC: 0.78 vs. 0.98). Only volumes created using a 2.5mm contraction from the outer surface, and a method providing a consistent wall volume, showed no notable dosimetric differences from BW_m in both absolute and relative volume.
Automatic contractions from the outer surface provide quicker, more reproducible and reasonably accurate substitutes for BW_m. The widespread use of automatic contractions to create a bladder wall volume would assist in the consistent application of IMRT dose constraints and the interpretation of reported dose.
Radiotherapy and Oncology 08/2011; 101(3):479-85. · 5.58 Impact Factor
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ABSTRACT: We have examined the role of VEGFC/VEGFR3 signaling in lymph node metastasis and growth of orthotopic human ME180 and SiHa cervical xenograft models following exposure to hypoxia. Our previous studies showed that growth of these tumors under conditions of cyclic hypoxia increased nodal metastasis.
Mice bearing orthotopic tumors were subjected to cyclic hypoxia at 7% O(2)/air 10min cycles 4h/day/2weeks. Knockdown of vegfc was carried out by shRNA and inhibition of VEGFR3 was conducted by blocking antibodies for the mouse and human proteins. VEGFR3 protein expression was detected by Western blotting. Immunohistochemical staining was used to assess CA9, CD31, LYVE1 and Ki67 labeling. Gene expression was determined by real time PCR.
Knock down of vegfc or inhibition of VEGFR3 with blocking antibody reduced metastases under normoxic and cyclic hypoxia conditions. A reduction in lymphatics and blood vessel formation and a decrease in tumor cell proliferation was observed following vegfc knockdown and VEGFR3 inhibition. VEGFR3 expression was upregulated at the mRNA and protein levels following hypoxia.
Collectively, our results indicate that anti-VEGFR3 antibody inhibits vegfc-induced tumor lymphangiogenesis and metastasis and that vegfc knockdown in the tumor cells causes a similar inhibitory effect on lymph node metastasis. These results suggest that the effects of vegfc/VEGFR3 on the progression of tumor cells to form lymph node metastases occur primarily under an hypoxic tumor microenvironment.
Gynecologic Oncology 08/2011; 123(2):393-400. · 3.89 Impact Factor
