A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Patterns of recurrence in genuine and induced oligometastatic castration-resistant prostate cancer treated with progressive site-directed therapy.

OBJECTIVES: To describe oncological outcomes after progressive site-directed therapy (PSDT) in genuine and induced oligometasatic (OM)-castration-resistant prostate cancer (CRPC). METHODS: Thirty-seven patients with OM-CRPC treated with PSDT were retrospectively analyzed, and oncological outcomes and recurrence patterns on whole-body diffusion-weighted MRI (WB-DWI) were evaluated. RESULTS: Twenty-two (59%) were classified as genuine OM-CRPC and 15 (41%) as induced OM-CRPC. A 50% decline in PSA after PSDT was observed in 21 (95%) genuine OM-CRPCs and 7 (47%) induced OM-CRPCs (p = 0.0005). At a median observation period of 7.3 months, median PSA progression-free survival were 10.9 months in the genuine OM-CRPCs and 4.8 months in the induced OM-CRPCs (p = 0.015). Among the patients who developed PSA progression after PSDT, 11 of 15 in the genuine OM-CRPCs (73%) and 11 of 14 in the induced OM-CRPCs (79%) underwent WB-DWI at PSA progression. The median numbers of newly detected metastases were 2 (range: 1-5) in the genuine OM-CRPCs and 4 (range: 1-40) in the induced OM-CRPCs (p = 0.049). Only one new metastasis appeared in 5 patients from the genuine OM-CRPCs (46%) and 1 from the induced OM-CRPCs (9.1%, p = 0.048). In 7 of 9 patients from the genuine OM-CRPCs (78%) and 7 of 8 patients from the induced OM-CRPCs (88%) who had bone metastases alone, the newly detected metastasis limited to the bone. CONCLUSIONS: Genuine OM-CRPC had better oncological outcomes after PSDT than induced OM-CRPC, and the number of lesions detected at recurrence was limited. Induced OM-CRPC might be a disseminated condition with micrometastases at OM diagnosis.

Metastatic Diffusion Volume Based on Apparent Diffusion Coefficient as a Prognostic Factor in Castration-Resistant Prostate Cancer.

BACKGROUND: Whole-body diffusion-weighted MRI (WB-DWI) is useful for assessing disease activity in castration-resistant prostate cancer (CRPC). MET-RADS-P is a subjective assessment-based reporting system proposed to standardize the interpretation of WB-DWI. However, a quantitative evaluation of WB-DWI has not been fully investigated. PURPOSE: To investigate the validity, and analyze the prognostic value, of quantitative evaluation of WB-DWI based on apparent diffusion coefficient (ADC) values for CRPC. STUDY TYPE: Retrospective. POPULATION: Sixty-six patients with CRPC. The median age was 75 years. During the median follow-up period of 25.2 months, 23 of 66 patients (34.8%) died of prostate cancer. FIELD STRENGTH/SEQUENCE: A 1.5 T WB-DWI was used with two b-values (0 s/mm2 -1000 s/mm2 ). A single-shot echo-planar imaging sequence was used. ASSESSMENT: WB-DWI were evaluated by three readers according to MET-RADS-P scoring system. Using imaging software, Attractive BDScore, tumor diffusion volume (mDV) and ADC value of metastatic lesion (mADC) was calculated by two readers. The mDV was calculated with ADC values (×10-3  mm2 /sec) of 0.4-0.9 (mDV0.4-0.9 ), 0.9-1.4 (mDV0.9-1.4 ), and 1.4-1.8 (mDV1.4-1.8 ), respectively. STATISTICAL TESTS: Spearman's rank correlation coefficient was used to assess the correlation. The relationships between the variables with cancer-specific survival (CSS) were evaluated. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: mDVs showed a strong positive correlation with MET-RADS-P scores (r = 0.90/0.87, P < 0.05 for both). mDV showed a statistically significant association with CSS (hazard ratio [HR]: 1.01, P < 0.05). When the mDVs calculated based on the ADC values were included, mDV0.4-0.9 (HR: 1.02, P < 0.05) and the number of therapeutic lines (HR: 1.35, P < 0.05) were significant independent indicators of CSS shortening. CONCLUSION: Assessment of metastatic tumor volume based on ADC values can be used in the prognostic evaluation of patients with CRPC. WB-DWI might be a potential prognostic imaging biomarker for CRPC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Potential of Perfusion Magnetic Resonance Imaging to Predict Residual Renal Function after Radical Nephroureterectomy.

INTRODUCTION: The diffusion-weighted imaging (DWI) technique with intravoxel incoherent motion model enables the estimation of capillary blood volume as a perfusion-related parameter- (PP-) value. Therefore, the PP-value of the kidney theoretically reflects renal capillary blood volume. We analyzed the usefulness of the PP-value in estimating postoperative renal function in upper-tract urothelial carcinoma (UTUC) patients. METHODS: Forty-eight consecutive patients who underwent magnetic resonance imaging before radical nephroureterectomy from 2011 to 2018 were analyzed. A PP-map displaying PP-values on a pixel-by-pixel basis was created from DWI signals (b-values of 0, 500, and 1,000 s/mm2). Two readers independently analyzed the renal PP-value. DWI-based split renal function (SRF) of the intact kidney was calculated by splitting serum Cr-based preoperative estimated glomerular filtration rates (eGFRs). The predictive accuracy of the method was evaluated using renography as the reference standard. RESULTS: Interobserver analysis revealed an excellent correlation value of 0.97. The SRF value showed a good linear correlation with the observed postoperative eGFR (r = 0.76, p < 0.001). The predictive accuracy of the DWI-based method was similar to that of the nuclear-based method. CONCLUSION: This DWI-based evaluation of capillary blood volume provides a noninvasive tool for predicting the postoperative renal function, thereby facilitating the management of UTUC patients.

Whole-body diffusion-weighted magnetic resonance imaging: Diagnosis and follow up of prostate cancer and beyond.

The diffusion-weighted imaging signal is derived from the motion of water molecules. It represents the physiological characteristics of tissue and is an essential imaging sequence for prostate cancer. Whole-body diffusion-weighted imaging facilitates the assessment of pathological conditions throughout the body. The concept of diffusion-weighted whole-body imaging with background body signal suppression and technological advances has led to routine clinical deployment of whole-body diffusion-weighted imaging as a one-step staging tool for prostate cancer. Furthermore, whole-body diffusion-weighted imaging has the potential to reveal the state of osseous lesions, for which conventional imaging techniques are suboptimal for monitoring the response to therapy, and extraosseous lesions, and holds promise as a new imaging-based therapeutic approach. This article reviews the basics of whole-body diffusion-weighted imaging, and focuses on application of whole-body diffusion-weighted imaging in the clinical management of prostate cancer at various stages in the course of the disease.

Usefulness of the inchworm sign on DWI for predicting pT1 bladder cancer progression.

OBJECTIVE: To evaluate the significance of the presence or absence of an "inchworm sign" on DWI for the recurrence and progression of T1 bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed 91 patients with pT1 urothelial carcinoma who underwent DWI prior to transurethral resection between 2007 and 2016. DWI of the dominant tumors was scrutinized for inchworm signs at b = 1000 s/mm2. The association of the presence of the inchworm sign with progression and recurrence was analyzed; progression was defined as recurrence to stage T2 or higher and/or N+, and/or M1. RESULTS: An inchworm sign was seen in 65 cases (71%), while it was absent in 26 cases. Among the 65, 25 (38%) had confirmed tumor recurrence, while in the remaining 26, 14 (54%) had confirmed recurrence (median time post TURB = 7.9 and 10.1 months for each). At the time of recurrence, the tumor had progressed in one (2%) inchworm-sign-positive and seven (27%) inchworm-sign-negative cases. The progression rate of inchworm-sign-negative cases was significantly higher than that of inchworm-sign-positive cases (hazard ratio = 17.2, p = 0.0017), whereas there was no significant difference in the recurrence rate between two groups. The absence of an inchworm sign and histological grade 3 were independent risk factors for progression (p < 0.001 and 0.010, respectively). CONCLUSIONS: The absence of an inchworm sign on DWI was a significant prognostic factor for progression of T1 bladder cancer. Morphological evaluation of DWI signals may therefore be a useful adjunct to preoperative assessment of biological aggressiveness. KEY POINTS: • An inchworm sign is a simple diagnostic criterion that characterizes only the shape of the tumor signal on DWI, and potentially serves as an imaging biomarker to predict clinical aggressiveness. • The absence of an inchworm sign on DWI is a significant indicator of progression of T1 bladder cancer.

Repeatability analysis of ADC histogram metrics of the uterus.

BACKGROUND: Recently, histogram analysis based on voxel-wise apparent diffusion coefficient (ADC) value distribution has been increasingly performed. However, few studies have been reported regarding its repeatability. PURPOSE: To evaluate the repeatability of ADC histogram metrics of the uterus in clinical magnetic resonance imaging (MRI). MATERIAL AND METHODS: Thirty-three female patients who underwent pelvic MRI including diffusion-weighted imaging (DWI) were prospectively included after providing informed consent. Two sequential DWI acquisitions with identical parameters and position were obtained. Regions of interest (ROIs) for histologically confirmed uterine lesions (five cervical and three endometrial cancers, and one endometrial hyperplasia) and normal appearing tissues (21 endometrium and 33 myometrium) were assigned on the first DWI dataset and then pasted onto the second DWI dataset. ADC histogram metrics within the ROIs were calculated and repeatability was evaluated by calculating within-subject coefficient of variance (%) (wCV (%)) and Bland-Altman plot (%). RESULTS: ADC 10%, 25%, median, 75%, 90%, maximum, mean, and entropy showed high repeatability (wCV (%) < 7, 95% limit of agreement in Bland-Altman plot (%) < ±20), followed by ADC minimum (wCV (%) = 8.12, 95% limit of agreement in Bland-Altman plot (%) < ±30). However, ADC skewness and kurtosis showed very low repeatability in all evaluations. CONCLUSION: ADC histogram metrics like ADC 10%, 25%, median, 75%, 90%, maximum, mean, and entropy are robust biomarkers and could be applicable to clinical use. However, ADC skewness and kurtosis lack robustness. Radiologists should keep these characteristics and limitations in mind when interpreting quantitative DWI.

Assessment of colonic contents in patients with chronic constipation using MRI.

Although chronic constipation is common, colonic functional evaluating tests are uncommon. This study examines whether chronic constipation and gastrointestinal symptoms are correlated with the lateral diameter of the colon measured from MRI images. We included chronic constipation patients in a prospective, cross-sectional study using MRI at three centers. We divided 3D MRI colorectal images into 6 segments using with specified sequences and selected the maximum luminal diameter from each segment. We used the GSRS questionnaire to evaluate gastrointestinal symptoms. We evaluated the correlation between luminal diameters and GSRS scores. We found the following positive correlations: descending colon and unsatisfactory defecation symptoms; sigmoid colon and diarrhea; and rectum and constipation. The sum and ratio of the ascending and sigmoid colon diameters correlated with nausea and diarrhea. The sum of the transvers to the sigmoid colon diameter also correlated with nausea and diarrhea. The sum of all segment diameters correlated with nausea and constipation. In conclusion, we showed cross-sectional study of colonic MRI correlate with gastrointestinal symptoms. MRI might be useful for colonic motility evaluations to determine appropriate constipation treatments (Clinical trial registry number UMIN 000021274).

Utility of computed diffusion-weighted MRI for predicting aggressiveness of prostate cancer.

PURPOSE: To investigate the value of computed (c) diffusion-weighted imaging (DWI) in assessing prostate cancer aggressiveness. MATERIALS AND METHODS: Fifty-five patients with peripheral zone prostate cancer who underwent prebiopsy 1.5T magnetic resonance imaging (including native DWI at b-values of 0 and 1000 s/mm2 ) were included. cDWI signal intensities of peripheral zone prostate cancer and nonmalignant prostate tissue were measured. Association between changes in monoexponentially calculated cDWI signals according to different b-values and primary Gleason grades were assessed. RESULTS: The cDWI signal intensity of prostate cancer was lower at b = 0 s/mm2 and higher at b = 1000 s/mm2 compared to nonmalignant prostate tissue. The b-value at which the signal intensities of prostate cancer and nonmalignant prostate tissue were equal was defined as the "iso-b-value." On multivariate analysis, only the iso-b-value was a significant predictor of primary Gleason grade 4/5 cancer (P = 0.001). The area under the curve (AUC) of the iso-b-value for diagnosing primary Gleason grade 4/5 cancer was 0.94, and significantly higher than that of the tumor apparent diffusion coefficient (ADC) value with an AUC of 0.68 (P < 0.001). CONCLUSION: cDWI with iso-b-value-based semiquantitative analysis was found to be useful for predicting the aggressiveness of prostate cancer and may potentially outperform tumor ADC measurements in this setting. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:490-496.

DWI as an Imaging Biomarker for Bladder Cancer.

OBJECTIVE: DWI has been increasingly applied in the management of bladder cancer. In this article, we discuss the role of DWI as an imaging biomarker for bladder cancer. CONCLUSION: The DWI signal is derived from the motion of water molecules, which represents the physiologic characteristics of the tissue of interest. The emerging evidence highlights the utility of DWI for bladder cancer detection and characterization. DWI is a potentially useful tool to individualize treatment strategies.

A Case of Hemi-ablation with High-intensity Focused Ultrasound for a Localized Reducted Solitary Lesion in the Prostate.

Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with high-intensity focused ultrasound (HIFU) for a patient with a localized reducted solitary lesion in the prostate, which was diagnosed with magnetic resonance imaging (MRI)-transrectal ultrasound fusion image-guided target biopsy with PSA level of 0.24 ng/mL, after androgen receptor signaling inhibitors (ARSIs) and chemotherapy for metastatic PC. Prostate specific antigen levels decreased to 0.01ng/mL at 1 month after the treatment, and cancer suspicious lesion disappeared on MRI. During the follow-up of 24 months, there was no elevation of PSA level with no severe complication related to the treatment. HIFU has possibility to be an effective and minimally invasive treatment as a local treatment for the localized reducted solitary lesion in the prostate after ARSIs and chemotherapy for metastatic PC.

Assessment of small bowel motility in patients with chronic intestinal pseudo-obstruction using cine-MRI.

OBJECTIVES: Chronic intestinal pseudo-obstruction (CIPO) is a rare, serious motility disorder, with life-threatening complications over time. However, lack of an established, non-invasive diagnostic method has caused delays in the diagnosis of this intractable disease. Cine-magnetic resonance imaging (MRI) is an emerging technique, with a potential to evaluate the motility of the entire bowel. We compared small bowel motility in healthy volunteers, patients with irritable bowel syndrome (IBS), and those with CIPO, using cine-MRI, and evaluated the usefulness of cine-MRI as a novel diagnostic method for CIPO. METHODS: Twelve healthy volunteers, IBS patients, and CIPO patients prospectively underwent cine-MRI at 1.5 T. Luminal diameter, contraction ratio, and contraction cycle were measured and compared between the groups. RESULTS: Cine-MRI provided sufficient dynamic images to assess the motility of the entire small bowel. Luminal diameter (mean±s.d.) in CIPO patients was significantly higher than that in healthy volunteers and IBS patients (43.4±14.1, 11.1±1.5, and 10.9±1.9 mm, respectively), and contraction ratio was significantly lower in CIPO patients than that in healthy volunteers and IBS patients (17.1±11.0%, 73.0±9.3%, and 74.6±9.4%, respectively). No significant differences were observed in the contraction cycle. CONCLUSIONS: This study is the first to assess the clinical utility of cine-MRI in CIPO patients. Cine-MRI clearly detected contractility impairments in CIPO patients. Cine-MRI is noninvasive, radiation-free, and can directly evaluate the entire small bowel peristalsis, and can detect the affected loops at a glance; therefore, it might be extremely useful for the diagnosis and follow-up of CIPO patients in clinical practice.

Computed diffusion-weighted imaging with a low-apparent diffusion coefficient-pixel cut-off technique for breast cancer detection.

OBJECTIVE: This study aimed to compare the image quality and diagnostic performance of computed diffusion-weighted imaging (DWI) with low-apparent diffusion coefficient (ADC)-pixel cut-off technique (cDWI cut-off) and actual measured DWI (mDWI). METHODS: Eighty-seven consecutive patients with malignant breast lesions and 72 with negative breast lesions who underwent breast MRI were retrospectively evaluated. Computed DWI with high b-values of 800, 1200, and 1500 s/mm2 and ADC cut-off thresholds of none, 0, 0.3, and 0.6 (×10-3 mm2/s) were generated from DWI with two b-values (0 and 800 s/mm2). To identify the optimal conditions, two radiologists evaluated the fat suppression and lesion reduction failure using a cut-off technique. The contrast between breast cancer and glandular tissue was evaluated using region of interest analysis. Three other board-certified radiologists independently assessed the optimised cDWI cut-off and mDWI data sets. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: When an ADC cut-off threshold of 0.3 or 0.6 (× 10-3 mm2/s) was applied, fat suppression improved significantly (p < .05). The contrast of the cDWI cut-off with a b-value of 1200 or 1500 s/mm2 was better than the mDWI (p < .01). The ROC area under the curve for breast cancer detection was 0.837 for the mDWI and 0.909 for the cDWI cut-off (p < .01). CONCLUSION: The cDWI cut-off provided better diagnostic performance than mDWI for breast cancer detection. ADVANCES IN KNOWLEDGE: Using the low-ADC-pixel cut-off technique, computed DWI can improve diagnostic performance by increasing contrast and eliminating un-suppressed fat signals.

Prostate and metastasis diffusion volume based on apparent diffusion coefficient as a prognostic factor in Hormone-naïve prostate Cancer.

In this study, to assess the utility of whole-body DWI (WB-DWI) as an imaging biomarker for metastatic hormone-naïve prostate cancer (mHNPC), we evaluated tumor diffusion volume based on apparent diffusion coefficient (ADC) values. WB-DWI results obtained from 62 mHNPC patients were evaluated in this retrospective analysis. The association with castration resistant-free survival (CFS) was evaluated for both prostate and metastatic tumor diffusion volume (pDV and mDV, respectively) based on WB-DWI. The usefulness of pDV and mDV based on ADC values to predict CFS was also examined. During the follow-up period, 22 patients progressed to castration-resistant prostate cancer, and the median CFS was 42.6 months. The median mDV and pDV were 6.7 and 12.6 mL, respectively. mDV was a significant predictor of CFS (hazard ratio [HR]: 2.75; p = 0.022), while pDV was not significant. When DV was divided into groups by ADC values (× 10- 3 mm2/s) of 0.4-1.0 and 1.0-1.8 (× 10- 3 mm2/s), mDV with ADC values (× 10- 3 mm2/s) of 0.4-1.0 (mDV0.4-1.0) showed a more favorable association with CFS compared to total mDV. On multivariate analysis, mDV0.4-1.0 and Gleason grade group had a statistically significant association with CFS (HR: 4.0; p = 0.004, and HR: 3.4; p = 0.006, respectively), while pDV with ADC values (× 10- 3 mm2/s) of 0.4-1.0 did not have a significant association. mDV is useful for predicting CFS in mHNPC patients. mDV may be a better imaging biomarker when based on ADC values.

Low b-value diffusion-weighted imaging: emerging applications in the body.

Thanks to recent advances in magnetic resonance imaging technology, it has become possible to perform intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in any part of the body. Extracranial applications of DWI are currently under active investigation, especially for oncological imaging. However, the use of non-quantitative low b-value (10-100 s/mm(2)) DWI in the body is still a relatively unexplored field, and its potential is not fully recognized. Non-quantitative low b-value DWI may especially be useful for the evaluation of structures that have an inherently low signal at high b-value DWI, including (but not limited to) the liver, heart, and small bowel. This article will review and discuss the basic principles and potential applications of nonquantitative low b-value DWI in the body.

T2-weighted and diffusion-weighted MRI for discriminating benign from malignant focal liver lesions: diagnostic abilities of single versus combined interpretations.

PURPOSE: To compare the diagnostic accuracies of diffusion-weighted imaging (DWI), T2-weighted imaging (T2WI), and the combination of both sequences in discriminating benign from malignant focal liver lesions (FLLs). MATERIALS AND METHODS: In all, 166 patients with 269 FLLs (153 benign and 116 malignant) were retrospectively evaluated. Two abdominal readers visually assessed the DWI, T2WI, and the combined (DWI+T2WI) image sets in an independent and blinded manner. The diagnostic abilities of each image set in discriminating the benign from the malignant FLLs set were compared using a binary logistic regression model. Pathologic results, consensus reading, and follow-up imaging were used as the reference standard. RESULTS: The overall characterization accuracy in all lesions of the combined set (80.3%) was significantly higher than those of the T2WI set (68.8%) and DWI set (73.2%) (combined vs. T2WI, P < 0.001; combined vs. DWI, P = 0.001), while there was no significant difference between the T2WI and DWI sets (P = 0.058). All image sets were more accurate in the characterization of malignant FLLs than of benign FLLs (P < 0.001). CONCLUSION: T2WI and DWI are complementary in discriminating benign from malignant FLLs; their combination improves diagnostic confidence.

Whole-body diffusion-weighted MRI: tips, tricks, and pitfalls.

OBJECTIVE: We examine the clinical impetus for whole-body diffusion-weighted MRI and discuss how to implement the technique with clinical MRI systems. We include practical tips and tricks to optimize image quality and reduce artifacts. The interpretative pitfalls are enumerated, and potential challenges are highlighted. CONCLUSION: Whole-body diffusion-weighted MRI can be used for tumor staging and assessment of treatment response. Meticulous technique and knowledge of potential interpretive pitfalls will help to avoid mistakes and establish this modality in radiologic practice.