Sharon L. Giles

Metastatic Ovarian and Primary Peritoneal Cancer: Assessing Chemotherapy Response with Diffusion-weighted MR Imaging—Value of Histogram Analysis of Apparent Diffusion Coefficients

PURPOSE To prospectively evaluate apparent diffusion coefficient (ADC) histograms in the prediction of chemotherapy response in patients with metastatic ovarian or primary peritoneal cancer. MATERIALS AND METHODS Research ethics committee approval and patient written informed consent were obtained. Diffusion-weighted (DW) magnetic resonance (MR) imaging was performed through the abdomen and pelvis before and after one and three cycles of chemotherapy in 42 women (mean age, 63.0 years ± 11.4 [standard deviation]) with newly diagnosed or recurrent disease. Reproducibility and intra- and interobserver agreement of ADC calculations were assessed. Per-patient weighted ADC histograms were generated at each time point from pixel ADCs from five or fewer target lesions. Mean ADC, percentiles (10th, 25th, 50th, 75th, 90th), skew, kurtosis, and their change were analyzed according to histologic grade, primary versus recurrent disease status, and response, determined with integrated biochemical and morphologic criteria, with a linear mixed model. Areas under receiver operating characteristic curve (AUCs) for combinations of parameters were calculated with linear discriminant analysis. RESULTS Coefficients of variation for repeat measurements and for within and between observers were 4.8%, 11.4%, and 13.7%, respectively. Grade and disease status did not significantly affect histogram parameters. Pretreatment ADCs were not predictive of response. In responders, all ADCs increased after the first and third cycle (P < .001), while skew and kurtosis decreased after the third (P < .001 and P = .006, respectively); however, in nonresponders, no parameter changed significantly. Percentage change of the 25th percentile performed best in identifying response (AUC = 0.82 and 0.83 after first and third cycle, respectively), whereas combination of parameters did not improve accuracy. CONCLUSION An early increase of ADCs and later decrease of skew and kurtosis characterize chemotherapy response. Quantitative DW MR imaging can aid in early monitoring of treatment efficacy in patients with advanced ovarian cancer.

Relationship Between Imaging Biomarkers of Stage I Cervical Cancer and Poor-Prognosis Histologic Features: Quantitative Histogram Analysis of Diffusion-Weighted MR Images

OBJECTIVE The purpose of this study was to determine whether histogram analysis of apparent diffusion coefficient (ADC) values from diffusion-weighted MRI can be used to differentiate cervical tumors according to their histologic characteristics. SUBJECTS AND METHODS Sixty patients with International Federation of Gynecology stage I cervical cancer underwent MRI at 1.5 T with a 37-mm-diameter endovaginal coil. T2-weighted images (TR/TE, 2000-2368/90) followed by diffusion-weighted images (TR/TE, 2500/69; b values, 0, 100, 300, 500, and 800 s/mm(2)) were acquired. An expert observer drew regions of interest around a histologically confirmed tumor on ADC maps by referring to the T2-weighted images. Pixel-by-pixel ADCs were calculated with a monoexponential fit of data from b values of 100-800 s/mm(2), and ADC histograms were obtained from the entire tumor volume. An independent samples Student t test was used to compare differences in ADC percentile values, skew, and kurtosis between squamous cell carcinoma and adenocarcinoma, well or moderately differentiated and poorly differentiated tumors, and absence and presence of lymphovascular space invasion. RESULTS There was no statistically significant difference in ADC percentiles between squamous cell carcinoma and adenocarcinoma, but the median was significantly higher in well or moderately differentiated tumors (50th percentile, 1113 ± 177 × 10(-6) mm(2)/s) compared with poorly differentiated tumors (50th percentile, 996 ± 184 × 10(-6) mm(2)/s) (p = 0.049). Histogram skew was significantly less positive for adenocarcinoma compared with squamous cell carcinoma (p = 0.016) but did not differ between tumor grades. There was no significant difference between any parameter with regard to lymphovascular space invasion. CONCLUSION Median ADC is lower in poorly compared with well or moderately differentiated tumors, while lower histogram-positive skew in adenocarcinoma compared with squamous cell carcinoma is likely to reflect the glandular content of adenocarcinoma.

Evaluation of magnetic resonance diffusion and spectroscopy measurements as predictive biomarkers in stage 1 cervical cancer

OBJECTIVE To establish whether ADC and total choline were significantly different between cervical tumors with different histological characteristics (type, degree of differentiation, presence or absence of lymphovascular invasion, lymph-node involvement) in order to establish their role as predictive biomarkers. METHODS 62 patients with stage 1 cervical cancer were scanned at 1.5 T. T2-weighted imaging (TR/TE=4500/80 ms), to identify tumor and normal cervix, was followed by diffusion-weighted imaging (TR/TE=2500/69 ms; 5 b-values 0, 100, 300, 500 and 800 s/mm(2)) and MR spectroscopic imaging (15 mm slice, 7.5 mm in-plane resolution, TR=888 ms). Regions of interest in normal cervix and tumor were drawn on apparent diffusion coefficient (ADC) maps by an expert observer with reference to the T2-weighted images. ADCs were calculated using a monoexponential fit of data from all b-values. MR spectra in voxels designated as tumor (>30% tumor) or non-tumor were quantified using LCModel and referenced to tissue water. RESULTS There was a statistically significant difference between the ADC of tumor regions (1117+/-183x10(-6) mm(2)/s) and of selected normal regions (1724+/-198x10(-6) mm(2)/s; p<0.001), and between tumors that were well/moderately differentiated (1196+/-181x10(-6) mm(2)/s) compared with those that were poorly differentiated (1038+/-153x10(-6) mm(2)/s; p=0.016). There was no significant difference between the ADCs of the tumors when separated by other characteristics (tumor type, lymphovascular invasion, lymph-node metastases), or between measured total choline in any of the groups. CONCLUSION ADCs are lower in cancer compared to normal cervical tissue, with degree of tumor differentiation contributing to this difference.

Diffusion-weighted magnetic resonance imaging for monitoring prostate cancer progression in patients managed by active surveillance

OBJECTIVES We studied patients managed by active surveillance to determine whether there was a difference over time in apparent diffusion coefficients (ADCs) derived from diffusion-weighted MRI in those who progressed to radical treatment (progressors, n = 17) compared with those who did not (non-progressors, n = 33). METHODS 50 consecutive patients (Stage T1/2a, Gleason grade ≤ 3+4, prostate-specific antigen (PSA) <15 ng ml⁻¹, <50% cores positive) were imaged endorectally (baseline and 1-3 years follow-up) with T₂ weighted (T₂W) and echo-planar diffusion-weighted MRI sequences. Regions of interest drawn on ADC maps with reference to the T₂W images yielded ADC(all) (b = 0-800), ADC(fast) (b = 0-300) and ADC(slow) (b = 300-800) for whole prostate (minus tumour) and tumour (low signal-intensity peripheral zone lesion in biopsy-positive octant). RESULTS Tumour and whole prostate ADC(all) and ADC(fast) were significantly reduced over time in progressors (p = 0.03 and 0.03 for tumours, respectively; p = 0.02 and 0.007 for the whole prostate, respectively). There were no significant changes in ADC over time in non-progressors. A 10% reduction in tumour ADC(all) indicated progression with a 93% sensitivity and 40% specificity (A(z) of receiver operating characteristic (ROC) curve = 0.68). Percentage reductions in whole prostate ADC(all), ADC(fast) and ADC(slow) were also significantly greater in progressors than in non-progressors (p = 0.01, 0.03 and 0.008, respectively). CONCLUSION This pilot study shows that DW-MRI has potential for monitoring patients with early prostate cancer who opt for active surveillance.

Diffusion-weighted Imaging of Peritoneal Disease for Noninvasive Staging of Advanced Ovarian Cancer

Cross-sectional imaging of peritoneal carcinomatosis in patients with advanced ovarian cancer is important for appropriate management but can be compromised by the small size of cancer implants and the complexity of anatomic relationships. Diffusion-weighted imaging is a functional magnetic resonance (MR) imaging technique that exploits the restricted water mobility within hypercellular tumors to increase the contrast between these lesions and surrounding tissue. Its use improves the detection and delineation of peritoneal implants at both initial staging and follow-up. Moreover, diffusion-weighted imaging provides quantitative information about tissue cellularity that may be used to distinguish viable tumors from treatment-related changes. These data allow calculation of apparent diffusion coefficient (ADC) values, which, when considered in conjunction with biochemical and morphologic parameters, are helpful for assessing the effectiveness of treatment. The value of diffusion-weighted images is maximized when they are interpreted in comparison with anatomic MR images to avoid diagnostic pitfalls arising from normal hypercellular structures and neoplasms with low cellularity. When incorporating diffusion-weighted imaging into abdominal and pelvic MR studies, it is important to be aware of the strengths and limitations of the technique. Competence in data display methods and ADC calculations also helps improve the accuracy of image interpretation and may aid in the management of patients with advanced ovarian cancer.

Whole-Body Diffusion-weighted MR Imaging for Assessment of Treatment Response in Myeloma

PURPOSE To determine the feasibility of whole-body diffusion-weighted (DW) magnetic resonance (MR) imaging for assessment of treatment response in myeloma. MATERIALS AND METHODS This prospective single-institution study was HIPAA-compliant with local research ethics committee approval. Written informed consent was obtained from each subject. Eight healthy volunteers (cohort 1a) and seven myeloma patients (cohort 1b) were imaged twice to assess repeatability of quantitative apparent diffusion coefficient (ADC) estimates. Thirty-four additional myeloma patients (cohort 2) underwent whole-body DW imaging before treatment; 26 completed a posttreatment imaging. Whole-body DW data were compared before and after treatment by using qualitative (ie, observer scores) and quantitative (ie, whole-body segmentation of marrow ADC) methods. Serum paraproteins and/or light chains or bone marrow biopsy defined response. RESULTS Whole-body DW imaging scores were significantly different between observers (P < .001), but change in scores between observers after treatment was not (P = .49). Sensitivity and specificity for detecting response according to observer scores were 86% (18 of 21 patients) and 80% (4 of 5 patients) for both observers. ADC measurement was repeatable: mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in myeloma patients. Pretreatment ADC in cohort 2 was significantly different from that in cohort 1a (P = .03), but not from that in cohort 1b (P = .2). Mean ADC increased in 95% (19 of 20) of responding patients and decreased in all (five of five) nonresponders (P = .002). A 3.3% increase in ADC helped identify response with 90% sensitivity and 100% specificity; an 8% increase (greater than repeatability of cohort 1b) resulted in 70% sensitivity and 100% specificity. There was a significant negative correlation between change in ADC and change in laboratory markers of response (r = -0.614; P = .001). CONCLUSION Preliminary work demonstrates whole-body DW imaging is a repeatable, quantifiable technique for assessment of treatment response in myeloma.

Assessing response of myeloma bone disease with diffusion-weighted MRI

OBJECTIVES To measure apparent diffusion coefficient (ADC) values in patients with active myeloma and remission and to determine whether changes differ in those responding/progressing on treatment. The relationship between changes in marrow fat and ADC was also explored. METHODS 20 patients were recruited. T(1 )weighted, T(2) weighted, short tau inversion-recovery, diffusion-weighted and two-point Dixon MRI of the lumbar spine and pelvis were performed at baseline, 4-6 weeks and 20 weeks. RESULTS ADC values of active disease (mean 761.2 ± 255×10(-6) mm(2) s(-1)) were significantly higher (p=0.047) than marrow in remission (mean 601.8 ± 459×10(-6) mm(2) s(-1)). Changes in ADC in responders showed a significant increase at 4-6 weeks (p=0.005) but no significant change between baseline and 20 weeks (p=0.733). ADCs in progressing and stable patients did not change significantly between either time point. Pearsons correlation coefficient between change in fat fraction and change in the number of pixels with an ADC of ≤655×10(-6) mm(2) s(-1) was 0.924, indicating a significant correlation (p<0.001). CONCLUSION ADC values in active myeloma are significantly higher than marrow in remission, indicating the potential for diffusion-weighted MRI to quantify the transition from active disease to remission and vice versa. This study confirms significant changes in ADC in patients responding to treatment and indirect evidence from two-point Dixon MRI suggests that these changes are influenced by changes in marrow fat. ADVANCES IN KNOWLEDGE ADC of active myeloma is significantly higher than marrow in remission; the direction of ADC changes on treatment is dependent on the timing of measurements and is influenced by changes in marrow fat.

Apparent Diffusion Coefficient as a Predictive Biomarker of Prostate Cancer Progression: Value of Fast and Slow Diffusion Components

OBJECTIVE The purpose of our study was to investigate whether fast and slow components of the apparent diffusion coefficient (ADC) from diffusion-weighted MR images could predict prostate cancer progression in patients managed by active surveillance. SUBJECTS AND METHODS Eighty-one patients managed by active surveillance underwent diffusion-weighted MRI in addition to T2-weighted MRI using an endorectal technique. ADCs from tumor regions of interest were calculated using all b values (ADC(all)), b = 0-300 s/mm(2) (ADC(fast)), and b = 300-800 s/mm(2) (ADC(slow)). These parameters and tumor volumes were compared in those upgraded at subsequent biopsy (n = 14) versus those histologically stable (n = 41) and in evaluable patients who progressed to radical treatment (n = 16) versus those who did not (n = 64). Coxs regression was used to analyze the effect of parameter mean on time to treatment. RESULTS ADC(all), ADC(fast), and ADC(slow) in patients upgraded on repeat biopsy were significantly lower than those who were stable (1,070 ± 110 vs 1,356 ± 357 × 10(-6)mm(2)/s, p < 0.001; 1,283 ± 188 vs 1,526 ± 397 × 10(-6)mm(2)/s, p = 0.004; 843 ± 74 vs 1,105 ± 285 × 10(-6) mm(2)/s, p < 0.001, respectively). Tumor volume was significantly higher in the upgraded group (0.86 ± 0.9 vs 0.26 ± 0.25 cm(3), p = 0.02). The lower ADC(slow) in patients who subsequently progressed to radical treatment approached significance (922 ± 256 vs 1,054 ± 235 × 10(-6) mm(2)/s, p = 0.053; hazard ratio, 0.991 for time to treatment). Tumor volume was significantly higher in the treated group (0.86 ± 0.85 cm(3) vs 0.32 ± 0.33 cm(3), p = 0.02). ADC(slow) and tumor volume were significant but independent predictors of upgrade on biopsy (p = 0.01 and 0.002, respectively). CONCLUSION Both fast and slow diffusion components were significantly lower in tumors that were subsequently upgraded on histology. Both tumor volume and the true diffusion ADC(slow) were significant but independent predictors of histologic progression.

Diffusion-Weighted MRI for Locally Recurrent Prostate Cancer After External Beam Radiotherapy

OBJECTIVE The objectives of our study were to establish the apparent diffusion coefficients (ADCs) of tumor and nontumor irradiated tissues in patients with suspected postradiation recurrence of prostate cancer and to determine the sensitivity and specificity of a combination of T2-weighted and diffusion-weighted imaging (DWI) for detecting local recurrence. MATERIALS AND METHODS Twenty-four patients with rising prostate-specific antigen levels after having completed radiation therapy 30-130 months earlier (median, 62 months) underwent endorectal T2-weighted imaging and DWI (b = 0, 100, 300, 500, and 800 s/mm(2)) followed by transrectal ultrasound (TRUS)-guided biopsy. Images were scored prospectively as positive for tumor if a region of low signal intensity on T2-weighted imaging within the prostate corresponded with a focally restricted area on the ADC map. A region of interest (ROI) was drawn around the suspicious lesion on a single slice of the ADC map and a corresponding ROI was drawn around presumed nontumor irradiated peripheral zone and central gland tissues on the opposite side of the prostate. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined against TRUS-guided biopsy reference standard (octant, n = 17; sextant, n = 5; two samples, n = 1; 12 samples, n = 1). RESULTS Sixteen of 24 patients (66.7%) had positive histology findings. The median tumor ROI area was 0.37 cm(2) (quartiles, 0.30 and 0.82 cm(2)). The sensitivity, specificity, PPV, and NPV for detecting tumor were 93.8%, 75%, 88.2%, and 85.7%, respectively. A cutoff ADC of 1216 × 10(-6) mm(2)/s could predict tumor with 100% sensitivity and 96% specificity (area under the receiver operating characteristic curve = 0.992). CONCLUSION An ADC derived from DWI is a useful adjunct to T2-weighted MRI for detecting local tumor recurrence larger than 0.4 cm(2) within the prostate.

Endovaginal magnetic resonance imaging of stage 1A/1B cervical cancer with A T2- and diffusion-weighted magnetic resonance technique: effect of lesion size and previous cone biopsy on tumor detectability.

OBJECTIVE To evaluate the effects of previous cone biopsy and lesion size on detectability of stage 1a/1b cervical cancer using endovaginal T2- and diffusion-weighted magnetic resonance imaging. METHODS One hundred and thirteen patients with cervical tumor were imaged using an endovaginal coil with T2-weighted (T2-W) and diffusion-weighted single-shot echo-planar sequences; 85 managed surgically (58 with prior cone biopsy/LLETZ) were evaluated. T2-W images and ADC maps viewed simultaneously were scored positive or negative for tumor and compared with histology at surgery. MRI tumor volumes, maximum radiological and histological dimensions were recorded. ROC analysis determined the MRI volume with optimal sensitivity/specificity for identifying tumor in those without and with prior cone biopsy/LLETZ and the maximum histological dimension for correctly identifying tumor with MRI. Mean apparent diffusion coefficients (ADCs) from tumor and adjacent normal epithelium were compared. RESULTS Sensitivity and specificity for detecting tumor in those without (100%; 100% respectively) and with (80%; 78.9% respectively) prior cone biopsy/LLETZ were significantly different (p<0.001). Following cone biopsy/LLETZ, MRI tumor volume of 83 mm3 detected tumor with 80% sensitivity, 94.7% specificity; a 5.3mm maximal histological dimension was detected on MRI with 100% sensitivity, 100% specificity. Tumor ADCs were significantly lower (p<0.001) than paired normal epithelial tissue (median, 988×10(-6) mm2/s vs. 1564×10(-6) mm2/s) but neither tumor nor epithelial ADCs differed significantly between patients with or without prior cone biopsy/LLETZ (p=0.48 and 0.15, respectively). CONCLUSIONS Endovaginal MRI with T2- and diffusion-weighted sequences has significantly lower sensitivity and specificity for tumor detection following cone biopsy/LLETZ.