A. Apte

Breast Cancer Subtype Intertumor Heterogeneity: MRI-Based Features Predict Results of a Genomic Assay

To investigate the association between a validated, gene‐expression‐based, aggressiveness assay, Oncotype Dx RS, and morphological and texture‐based image features extracted from magnetic resonance imaging (MRI).

Treatment planning constraints to avoid xerostomia in head-and-neck radiotherapy: an independent test of QUANTEC criteria using a prospectively collected dataset.

PURPOSE The severe reduction of salivary function (xerostomia) is a common complication after radiation therapy for head-and-neck cancer. Consequently, guidelines to ensure adequate function based on parotid gland tolerance dose-volume parameters have been suggested by the QUANTEC group and by Ortholan et al. We perform a validation test of these guidelines against a prospectively collected dataset and compared with a previously published dataset. METHODS AND MATERIALS Whole-mouth stimulated salivary flow data from 66 head-and-neck cancer patients treated with radiotherapy at the British Columbia Cancer Agency (BCCA) were measured, and treatment planning data were abstracted. Flow measurements were collected from 50 patients at 3 months, and 60 patients at 12-month follow-up. Previously published data from a second institution, Washington University in St. Louis (WUSTL), were used for comparison. A logistic model was used to describe the incidence of Grade 4 xerostomia as a function of the mean dose of the spared parotid gland. The rate of correctly predicting the lack of xerostomia (negative predictive value [NPV]) was computed for both the QUANTEC constraints and Ortholan et al. recommendation to constrain the total volume of both glands receiving more than 40 Gy to less than 33%. RESULTS Both datasets showed a rate of xerostomia of less than 20% when the mean dose to the least-irradiated parotid gland is kept to less than 20 Gy. Logistic model parameters for the incidence of xerostomia at 12 months after therapy, based on the least-irradiated gland, were D(50) = 32.4 Gy and and γ = 0.97. NPVs for QUANTEC guideline were 94% (BCCA data), and 90% (WUSTL data). For Ortholan et al. guideline NPVs were 85% (BCCA) and 86% (WUSTL). CONCLUSION These data confirm that the QUANTEC guideline effectively avoids xerostomia, and this is somewhat more effective than constraints on the volume receiving more than 40 Gy.

Breast cancer molecular subtype classifier that incorporates MRI features.

To use features extracted from magnetic resonance (MR) images and a machine‐learning method to assist in differentiating breast cancer molecular subtypes.

Clinical and dosimetric predictors of acute hematologic toxicity in rectal cancer patients undergoing chemoradiotherapy

BACKGROUND AND PURPOSE To identify clinical and dosimetric factors associated with hematologic toxicity (HT) during chemoradiotherapy for rectal cancer. MATERIALS AND METHODS We analyzed 120 rectal cancer patients treated with neoadjuvant pelvic radiotherapy (PRT) with concurrent 5-fluorouracil-based chemotherapy. The coxal (ilium, ischium, and pubis) bone marrow (BM), sacral BM, and femoral BM were contoured and dose-volume parameters were extracted. Associations between cell count trend and clinical predictors were tested using repeated-measures analysis of variance (ANOVA) test. Associations between clinical variables, Vx (percentage volume receiving x Gy), and cell count ratio at nadir were tested using linear regression models. RESULTS Nadirs for white blood cell count (WBC), absolute neutrophil count (ANC), and platelets (PLT) occurred in the second week of PRT and the fifth week for hemoglobin and absolute lymphocyte count (ALC). Using cell count ratio, patients treated with 3DCRT had a lower WBC ratio trend during PRT compared to patients treated with IMRT (p=0.04), and patients ⩾59 years of age had a lower hemoglobin ratio trend during PRT (p=0.02). Using absolute cell count, patients treated with 3DCRT had lower ANC cell count trend (p=0.03), and women had lower hemoglobin cell count trend compared to men (p=0.03). On univariate analysis, use of 3DCRT was associated with a lower WBC ratio at nadir (p=0.02). On multiple regression analysis using dosimetric variables, coxal BM V45 (p=0.03) and sacral BM V45 (p=0.03) were associated with a lower WBC and ANC ratio at nadir, respectively. CONCLUSIONS HT trends during PRT revealed distinct patterns: WBC, ANC, and PLT cell counts reach nadirs early and recover, while hemoglobin and ALC decline steadily. Patients who were treated with 3DCRT and older patients experienced lower cell count ratio trend during PRT. Dosimetric constraints using coxal BM V45 and sacral BM V45 can be considered.

Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiotherapy.

Abstract Background and purpose. Internal organ motion over a course of radiotherapy (RT) leads to uncertainties in the actual delivered dose distributions. In studies predicting RT morbidity, the single estimate of the delivered dose provided by the treatment planning computed tomography (pCT) is typically assumed to be representative of the dose distribution throughout the course of RT. In this paper, a simple model for describing organ motion is introduced, and is associated to late rectal morbidity data, with the aim of improving morbidity prediction. Material and methods. Organ motion was described by normally distributed translational motion, with its magnitude characterised by the standard deviation (SD) of this distribution. Simulations of both isotropic and anisotropic (anterior-posterior only) motion patterns were performed, as were random, systematic or combined random and systematic motion. The associations between late rectal morbidity and motion-inclusive delivered dose-volume histograms (dDVHs) were quantified using Spearmans rank correlation coefficient (Rs) in a series of 232 prostate cancer patients, and were compared to the associations obtained with the static/planned DVH (pDVH). Results. For both isotropic and anisotropic motion, different associations with rectal morbidity were seen with the dDVHs relative to the pDVHs. The differences were most pronounced in the mid-dose region (40–60 Gy). The associations were dependent on the applied motion patterns, with the strongest association with morbidity obtained by applying random motion with an SD in the range 0.2–0.8 cm. Conclusion. In this study we have introduced a simple model for describing organ motion occurring during RT. Differing and, for some cases, stronger dose-volume dependencies were found between the motion-inclusive dose distributions and rectal morbidity as compared to the associations with the planned dose distributions. This indicates that rectal organ motion during RT influences the efforts to model the risk of morbidity using planning distributions alone.

PET quantification with a histogram derived total activity metric: superior quantitative consistency compared to total lesion glycolysis with absolute or relative SUV thresholds in phantoms and lung cancer patients.

INTRODUCTION The increasing use of molecular imaging probes as biomarkers in oncology emphasizes the need for robust and stable methods for quantifying tracer uptake in PET imaging. The primary motivation for this research was to find an accurate method to quantify the total tumor uptake. Therefore we developed a histogram-based method to calculate the background subtracted lesion (BSL) activity and validated BSL by comparing the quantitative consistency with the total lesion glycolysis (TLG) in phantom and patient studies. METHODS A thorax phantom and a PET-ACR quality assurance phantom were scanned with increasing FDG concentrations. Volumes of interest (VOIs) were placed over each chamber. TLG was calculated with a fixed threshold at SUV 2.5 (TLG2.5) and a relative threshold at 42% of SUVmax (TLG42%). The histogram for each VOI was built and BSL was calculated. Comparison with the total injected FDG activity (TIA) was performed using concordance correlation coefficients (CCC) and the slope (a). Fifty consecutive patients with FDG-avid lung tumors were selected under an IRB waiver. TLG42%, TLG2.5 and BSL were compared to the reference standard calculating CCC and the slope. RESULTS In both phantoms, the CCC for lesions with a TIA ≤50ml*SUV between TIA and BSL was higher and the slope closer to 1 (CCC=0.933, a=1.189), than for TLG42% (CCC=0.350, a=0.731) or TLG2.5 (CCC=0.761, a=0.727). In 50 lung lesions BSL had a slope closer to 1 compared to the reference activity than TLG42% (a=1.084 vs 0.618 - for high activity lesions) and also closer to 1 than TLG2.5 (a=1.117 vs 0.548 - for low activity lesions). CONCLUSION The histogram based BSL correlated better with TIA in both phantom studies than TLG2.5 or TLG42%. Also in lung tumors, the BSL activity is overall more accurate in quantifying the lesion activity compared to the two most commonly applied TLG quantification methods.

Dose/volume-response relations for rectal morbidity using planned and simulated motion-inclusive dose distributions.

BACKGROUND AND PURPOSE Many dose-limiting normal tissues in radiotherapy (RT) display considerable internal motion between fractions over a course of treatment, potentially reducing the appropriateness of using planned dose distributions to predict morbidity. Accounting explicitly for rectal motion could improve the predictive power of modelling rectal morbidity. To test this, we simulated the effect of motion in two cohorts. MATERIALS AND METHODS The included patients (232 and 159 cases) received RT for prostate cancer to 70 and 74 Gy. Motion-inclusive dose distributions were introduced as simulations of random or systematic motion to the planned dose distributions. Six rectal morbidity endpoints were analysed. A probit model using the QUANTEC recommended parameters was also applied to the cohorts. RESULTS The differences in associations using the planned over the motion-inclusive dose distributions were modest. Statistically significant associations were obtained with four of the endpoints, mainly at high doses (55-70 Gy), using both the planned and the motion-inclusive dose distributions, primarily when simulating random motion. The strongest associations were observed for GI toxicity and rectal bleeding (Rs=0.12-0.21; Rs=0.11-0.20). Applying the probit model, significant associations were found for tenesmus and rectal bleeding (Rs=0.13, p=0.02). CONCLUSION Equally strong associations with rectal morbidity were observed at high doses (>55 Gy), for the planned and the simulated dose distributions including in particular random rectal motion. Future studies should explore patient-specific descriptions of rectal motion to achieve improved predictive power.

Multi‐institutional validation of a novel textural analysis tool for preoperative stratification of suspected thyroid tumors on diffusion‐weighted MRI

Ultrasound‐guided fine needle aspirate cytology fails to diagnose many malignant thyroid nodules; consequently, patients may undergo diagnostic lobectomy. This study assessed whether textural analysis (TA) could noninvasively stratify thyroid nodules accurately using diffusion‐weighted MRI (DW‐MRI).

Predictors of acute toxicities during definitive chemoradiation using intensity-modulated radiotherapy for anal squamous cell carcinoma

Purpose. To identify clinical and dosimetric factors associated with acute hematologic and gastrointestinal (GI) toxicities during definitive therapy using intensity-modulated radiotherapy (IMRT) for anal squamous cell carcinoma (ASCC). Materials and methods. We retrospectively analyzed 108 ASCC patients treated with IMRT. Clinical information included age, gender, stage, concurrent chemotherapy, mitomycin (MMC) chemotherapy and weekly hematologic and GI toxicity during IMRT. From contours of the bony pelvis and bowel, dose-volume parameters were extracted. Logistic regression models were used to test associations between toxicities and clinical or dosimetric predictors. Results. The median age was 59 years, 81 patients were women and 84 patients received concurrent MMC and 5-fluorouracil (5FU). On multivariate analysis (MVA), the model most predictive of Grade 2 + anemia included the maximum bony pelvis dose (Dmax), female gender, and T stage [p = 0.035, cross validation area under the curve (cvAUC) = 0.66]. The strongest model of Grade 2 + leukopenia included V10 (percentage of pelvic bone volume receiving ≥ 10 Gy) and number of MMC cycles (p = 0.276, cvAUC = 0.57). The model including MMC cycle number and T stage correlated best with Grade 2 + neutropenia (p = 0.306, cvAUC = 0.57). The model predictive of combined Grade 2 + hematologic toxicity (HT) included V10 and T stage (p = 0.016, cvAUC = 0.66). A model including VA45 (absolute bowel volume receiving ≥ 45 Gy) and MOH5 (mean dose to hottest 5% of bowel volume) best predicted diarrhea (p = 0.517, cvAUC = 0.56). Conclusion. Dosimetric constraints to the pelvic bones should be integrated into IMRT planning to reduce toxicity, potentially reducing treatment interruptions and improving disease outcomes in ASCC. Specifically, our results indicate that Dmax should be confined to ≤ 57 Gy to minimize anemia and that V10 should be restricted to ≤ 87% to reduce incidence of all HT.

Feasibility of In Situ, High-Resolution Correlation of Tracer Uptake with Histopathology by Quantitative Autoradiography of Biopsy Specimens Obtained Under 18F-FDG PET/CT Guidance

Core biopsies obtained using PET/CT guidance contain bound radiotracer and therefore provide information about tracer uptake in situ. Our goal was to develop a method for quantitative autoradiography of biopsy specimens (QABS), to use this method to correlate 18F-FDG tracer uptake in situ with histopathology findings, and to briefly discuss its potential application. Methods: Twenty-seven patients referred for a PET/CT-guided biopsy of 18F-FDG–avid primary or metastatic lesions in different locations consented to participate in this institutional review board–approved study, which complied with the Health Insurance Portability and Accountability Act. Autoradiography of biopsy specimens obtained using 5 types of needles was performed immediately after extraction. The response of autoradiography imaging plates was calibrated using dummy specimens with known activity obtained using 2 core-biopsy needle sizes. The calibration curves were used to quantify the activity along biopsy specimens obtained with these 2 needles and to calculate the standardized uptake value, SUVARG. Autoradiography images were correlated with histopathologic findings and fused with PET/CT images demonstrating the position of the biopsy needle within the lesion. Logistic regression analysis was performed to search for an SUVARG threshold distinguishing benign from malignant tissue in liver biopsy specimens. Pearson correlation between SUVARG of the whole biopsy specimen and average SUVPET over the voxels intersected by the needle in the fused PET/CT image was calculated. Results: Activity concentrations were obtained using autoradiography for 20 specimens extracted with 18- and 20-gauge needles. The probability of finding malignancy in a specimen is greater than 50% (95% confidence) if SUVARG is greater than 7.3. For core specimens with preserved shape and orientation and in the absence of motion, one can achieve autoradiography, CT, and PET image registration with spatial accuracy better than 2 mm. The correlation coefficient between the mean specimen SUVARG and SUVPET was 0.66. Conclusion: Performing QABS on core-biopsy specimens obtained using PET/CT guidance enables in situ correlation of 18F-FDG tracer uptake and histopathology on a millimeter scale. QABS promises to provide useful information for guiding interventional radiology procedures and localized therapies and for in situ high-spatial-resolution validation of radiopharmaceutical uptake.