Safety and efficacy of MRI-guided transurethral ultrasound ablation for radiorecurrent prostate cancer in the presence of gold fiducial markers.

BACKGROUND: Safety and efficacy of ultrasound prostate ablation for radiorecurrent prostate cancer (PCa) in the presence of gold fiducial markers has not been previously reported. PURPOSE: To evaluate safety, functional, and early-stage oncological outcomes for patients with gold fiducial markers undergoing salvage magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (sTULSA) for radiorecurrent PCa. MATERIAL AND METHODS: Data were acquired from an ethics-approved, single-center phase-1 study. Eight patients with 18 total gold fiducial markers inside the planned treatment volume were identified. MRI controls were performed at three and 12 months, followed by PSMA-PET-CT imaging and biopsies at 12 months. A control cohort of 13 patients who underwent sTULSA without markers were also identified for safety profile comparison. Adverse events were reported using the Clavien-Dindo classification, and questionnaires including EPIC-26, IPSS, and IIEF-5 were collected. RESULTS: Of 18 markers, 2 (11%) were directly responsible for poor ultrasound penetration. However, there were no local recurrences at 12 months. PSA, prostate volume, and non-perfused volume all decreased over time. At 12 months, 11/18 (61%) of fiducial markers had disappeared via sloughing. The adverse event profile was similar between both patient cohorts, and when controlled for ablation type, no statistical difference in functional outcomes between the two cohorts was observed. CONCLUSION: Patients with radiorecurrent PCa with intraprostatic gold fiducial markers can be successfully treated with TULSA. The early-stage efficacy of sTULSA for patients with intraprostatic gold markers is encouraging and the safety profile is unaffected by marker presence.

Magnetic resonance imaging-guided transurethral ultrasound ablation for benign prostatic hyperplasia: 12-month clinical outcomes of a phase I study.

OBJECTIVES: To investigate the safety and feasibility of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) for the treatment of benign prostatic obstruction (BPO). PATIENTS AND METHODS: An investigator-initiated, prospective, registered (NCT03350529), phase I study enrolled men with lower urinary tract symptoms due to benign prostatic hyperplasia in need of surgical intervention. Patients were followed for 12 months after TULSA. Uroflowmetry, prostate-specific antigen (PSA) level, and a comprehensive set of functional questionnaires including the Expanded Prostate cancer Index Composite-26, International Prostate Symptom Score (IPSS) and five-item version of the International Index of Erectile Function were obtained at baseline and every 3 months afterwards. MRI was obtained at baseline, and at 3 and 12 months after TULSA. Medication use before and after TULSA were recorded. Adverse events (AEs) were reported using the Clavien-Dindo classification. RESULTS: A total of 10 men underwent TULSA with no severe AEs encountered. The baseline median (interquartile range [IQR]) age and prostate volume were 68 (63-72) years and 53 (45-66) mL, respectively. At baseline, six patients were moderately symptomatic and four patients severely symptomatic. Nine patients at baseline were on BPO medication. The median (IQR) improvement in the IPSS was 82%, from 17.5 (15.3-23.0) at baseline to 4.0 (2.3-6.3) at 12 months. Similarly, the median maximum urinary flow rate improved by 101%, from a median (IQR) of 12.4 (8.8-17.6) mL/s at baseline to 21.8 (17.6-26.5) mL/s at 12 months. Improvements were already seen at 3 months. The median prostate volume and PSA reduction at 12 months were 33% and 48%, respectively. There were no changes in continence, sexual, erectile or bowel functions. At 12 months, five out of six men with normal ejaculatory function before TULSA reported normal antegrade ejaculations. All patients taking BPO medication before TULSA discontinued medication after TULSA. CONCLUSION: TULSA appears to be a safe and effective treatment for BPO, with promising 12-month follow-up outcomes. Further studies with larger cohorts are needed to confirm the observed results.

Fiducial markers and their impact on ablation outcome for patients treated with MR-guided transurethral ablation (TULSA): a retrospective technical analysis.

OBJECTIVES: Fiducial markers improve accuracy in external beam radiation therapy (EBRT) for treatment of prostate cancer (PCa). However, many patients recur after EBRT necessitating additional treatment, such as MR-guided transurethral ultrasound ablation (TULSA). Residual markers may compromise TULSA through ultrasound field distortions and generation of local susceptibility artifacts. The objective was to investigate how markers affect the ablation outcome during clinical TULSA treatments. SUBJECTS AND METHODS: A retrospective analysis was performed on nine patients with radiorecurrent PCa and residual markers who received TULSA. The MR susceptibility artifact was quantified as a function of marker type, size and orientation, in particular for thermometry. The spatial distribution of markers inside the prostate was recorded, and the resulting impact on the thermal dose was measured. The thermal dose measurements were directly compared to the residual enhancing prostatic tissue observed on the immediate and control post-TULSA contrast enhanced (CE) image. RESULTS: Successful thermal dose accumulation to the target boundary occurred for 14/20 (70%) of markers, confirmed with CE imaging. Gold markers situated simultaneously close to the urethra (≤12 mm) and far from the target boundary (≥13 mm) reduced the ultrasound depth of heating. Nitinol markers produced large, hypointense artifacts that disrupted thermometry and compromised treatment. Artifacts from gold markers were less pronounced, but when located near the target boundary, also affected treatment. CONCLUSION: Marker composition, orientation and location inside the prostate can all potentially impact treatment outcome. Proper patient selection through detailed MRI screening is critical to ensure successful radiorecurrent PCa treatment outcomes with TULSA.

Acute and subacute prostate MRI findings after MRI-guided transurethral ultrasound ablation of prostate cancer.

BACKGROUND: Magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) is an emerging method for treatment of localized prostate cancer (PCa). TULSA-related subacute MRI findings have not been previously characterized. PURPOSE: To evaluate acute and subacute MRI findings after TULSA treatment in a treat-and-resect setting. MATERIAL AND METHODS: Six men with newly diagnosed MRI-visible and biopsy-concordant clinically significant PCa were enrolled and completed the study. Eight lesions classified as PI-RADS 3-5 were focally ablated using TULSA. One- and three-week follow-up MRI scans were performed between TULSA and robot-assisted laparoscopic prostatectomy. RESULTS: TULSA-related hemorrhage was detected as a subtle T1 hyperintensity and more apparent T2 hypointensity in the MRI. Both prostate volume and non-perfused volume (NPV) markedly increased after TULSA at one week and three weeks after treatment, respectively. Lesion apparent diffusion coefficient values increased one week after treatment and decreased nearing the baseline values at the three-week MRI follow-up. CONCLUSION: The optimal timing of MRI follow-up seems to be at the earliest at three weeks after treatment, when the post-procedural edema has decreased and the NPV has matured. Diffusion-weighted imaging has little or no added diagnostic value in the subacute setting.

Histopathological evaluation of prostate specimens after thermal ablation may be confounded by the presence of thermally-fixed cells.

Purpose: Prostate cancer can be eradicated with heat exposure. However, high and rapid temperature elevations may cause thermofixation giving the appearance of viable tissue. The purpose was to characterize the immunoprofile and evaluate the viability of prostate regions with suspected thermofixation. Methods and materials: A prospective, ethics-approved and registered study (NCT03350529) enrolled six patients with MRI-visible, biopsy-concordant prostate cancer to undergo lesion-targeted MRI-guided transurethral ultrasound ablation (TULSA) followed by radical prostatectomy at 3 weeks, to evaluate the accuracy and efficacy of TULSA with whole-mount histology as a reference standard. If ambiguity about complete necrosis within the ablated region remained after hematoxylin-eosin staining, viability was assessed by immunohistochemistry. Treatment day MRI-thermometry and 3-week contrast-enhanced MRI post-TULSA were examined to assess ablation success and correlation with histopathology. Results: One patient presented with an apparently viable subregion inside the ablated area, surrounded by necrosis on H&E staining, located where temperature was highest on MRI-thermometry and tissues completely devascularized on MRI. Immunoprofile of the apparently viable tissue revealed changes in staining patterns suggesting thermofixation; the most significant evidence was the negative cytokeratin 8 staining detected with Cam5.2 antibody. A comprehensive literature review supports these observations of thermofixation with similar findings in prostate and other tissues. Conclusion: Thermally-fixed cells can sustain morphology on H&E staining. Misinterpretation of treatment failure may occur, if this phenomenon is not recognized and immunohistochemistry performed. Based on the previous literature and the current study, Cam5.2 staining for cytokeratin 8 appears to be a practical and reliable tool for distinguishing thermally-fixed from viable cells.

Evolution of non-perfused volume after transurethral ultrasound ablation of prostate: A retrospective 12-month analysis.

Background: A detailed understanding of the non-perfused volume (NPV) evolution after prostate ablation therapy is lacking. The impact of different diseased prostate tissues on NPV evolution post-ablation is unknown. Purpose: To characterize the NPV evolution for three treatment groups undergoing heat-based prostate ablation therapy, including benign prostatic hyperplasia (BPH), primary prostate cancer (PCa), and radiorecurrent PCa. Materials and methods: Study design and data analysis were performed retrospectively. All patients received MRI-guided transurethral ultrasound ablation (TULSA). 21 BPH, 28 radiorecurrent PCa and 40 primary PCa patients were included. Using the T1-weighted contrast-enhanced MR image, the NPV was manually contoured by an experienced radiologist. All patients received an MRI immediately following the ablation. Follow-up included MRI at 3- and 12 months for BPH and radiorecurrent PCa patients and at 6- and 12 months for primary PCa patients. Results: A significant difference between BPH and radiorecurrent PCa patients was observed at three months (p < 0.0001, Wilcoxon rank sum test), with the median NPV decreasing by 77 % for BPH patients but increasing by 4 % for radiorecurrent PCa patients. At six months, the median NPV decreased by 97 % for primary PCa. Across all groups, although 40 % of patients had residual NPV at 12 months, it tended to be < 1 mL. Conclusion: The resolution of necrotic tissue after ablation was markedly slower for irradiated than treatment-naïve prostate tissue. These results may account for the increased toxicity observed after radiorecurrent salvage therapy. By 12 months, most necrotic prostate tissue had disappeared in every treatment group.

Deep learning prediction of non-perfused volume without contrast agents during prostate ablation therapy.

The non-perfused volume (NPV) is an important indicator of treatment success immediately after prostate ablation. However, visualization of the NPV first requires an injection of MRI contrast agents into the bloodstream, which has many downsides. Purpose of this study was to develop a deep learning model capable of predicting the NPV immediately after prostate ablation therapy without the need for MRI contrast agents. A modified 2D deep learning UNet model was developed to predict the post-treatment NPV. MRI imaging data from 95 patients who had previously undergone prostate ablation therapy for treatment of localized prostate cancer were used to train, validate, and test the model. Model inputs were T1/T2-weighted and thermometry MRI images, which were always acquired without any MRI contrast agents and prior to the final NPV image on treatment-day. Model output was the predicted NPV. Model accuracy was assessed using the Dice-Similarity Coefficient (DSC) by comparing the predicted to ground truth NPV. A radiologist also performed a qualitative assessment of NPV. Mean (std) DSC score for predicted NPV was 85% ± 8.1% compared to ground truth. Model performance was significantly better for slices with larger prostate radii (> 24 mm) and for whole-gland rather than partial ablation slices. The predicted NPV was indistinguishable from ground truth for 31% of images. Feasibility of predicting NPV using a UNet model without MRI contrast agents was clearly established. If developed further, this could improve patient treatment outcomes and could obviate the need for contrast agents altogether. Trial Registration Numbers Three studies were used to populate the data: NCT02766543, NCT03814252 and NCT03350529. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-022-00250-y.

Salvage Magnetic Resonance Imaging-guided Transurethral Ultrasound Ablation for Localized Radiorecurrent Prostate Cancer: 12-Month Functional and Oncological Results.

BACKGROUND: Up to half of all men who undergo primary radiotherapy for localized prostate cancer (PCa) experience local recurrence. OBJECTIVE: To evaluate the safety and early functional and oncological outcomes of salvage magnetic resonance imaging-guided transurethral ultrasound ablation (sTULSA) for men with localized radiorecurrent PCa. DESIGN SETTING AND PARTICIPANTS: This prospective, single-center phase 1 study (NCT03350529) enrolled men with biopsy-proven localized PCa recurrence after radiotherapy. Multiparametric magnetic resonance imaging (mpMRI) and 18F prostate-specific membrane antigen-1007 (18F PSMA-1007) positron emission tomography (PET)-computed tomography (CT) were used to confirm organ-confined disease localization. Patients underwent either whole-gland or partial sTULSA, depending on their individual tumor characteristics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were followed at 3-mo intervals. Adverse events (AEs, Clavien-Dindo scale), functional status questionnaires (Expanded Prostate Cancer Index [EPIC]-26, International Prostate Symptom Score, International Index of Erectile Function-5), uroflowmetry, and prostate-specific antigen (PSA) were assessed at every visit. Disease control was assessed at 1 yr using mpMRI and 18F-PSMA-1007 PET-CT, followed by prostate biopsies. RESULTS AND LIMITATIONS: Eleven patients (median age 69 yr, interquartile range [IQR] 68-74) underwent sTULSA (3 whole-gland, 8 partial sTULSA) and have completed 12-mo follow-up. Median PSA was 7.6 ng/ml (IQR 4.9-10) and the median time from initial PCa diagnosis to sTULSA was 11 yr (IQR 9.5-13). One grade 3 and three grade 2 AEs were reported, related to urinary retention and infection. Patients reported a modest degradation in functional status, most significantly a 20% decline in the EPIC-26 irritative/obstructive domain at 12 mo. A decline in maximum flow rate (24%) was also observed. At 1 yr, 10/11 patients were free of any PCa in the targeted ablation zone, with two out-of-field recurrences. Limitations include the nonrandomized design, limited sample size, and short-term oncological outcomes. CONCLUSIONS: sTULSA appears to be safe and feasible for ablation of radiorecurrent PCa, offering encouraging preliminary oncological control. PATIENT SUMMARY: We present safety and 1-yr functional and oncological outcomes of magnetic resonance imaging-guided transurethral ultrasound ablation (TULSA) as a salvage treatment for local prostate cancer recurrence after primary radiation. Salvage TULSA is safe and shows the ability to effectively ablate prostate cancer recurrence, with acceptable toxicity.

Palliative MRI-guided transurethral ultrasound ablation for symptomatic locally advanced prostate cancer.

PURPOSE: Locally advanced prostate cancer can cause bladder outlet obstruction, gross hematuria and frequent hospitalization. While these complications are commonly treated by palliative transurethral resection of the prostate, the improvement is often insufficient. The purpose of this study was to evaluate the safety and feasibility of MRI-guided transurethral ultrasound ablation as an alternative palliative treatment option (pTULSA) for men suffering from symptomatic locally advanced prostate cancer. METHODS: This prospective, phase one study included 10 men in need of palliative surgical intervention due to urinary retention and gross hematuria caused by locally advanced prostate cancer. Patients were followed for 1 year at 3-month intervals. Time without catheter, time without hematuria, reduction in hospitalization time, and adverse events were measured. RESULTS: Ten patients with locally advanced prostate cancer were enrolled, all having continuous catheterization due to urinary retention and nine had gross hematuria before treatment. At 1 week post-pTULSA five patients were catheter-free. At last follow-up catheter-free and gross hematuria-free rates were 70% and 100%, respectively. Average hospitalization time from local complications reduced from 7.3 to 1.4 days in the 6 months before and after pTULSA. No > Grade 2 treatment related adverse events were reported, with all five being urinary tract infections. CONCLUSIONS: pTULSA appears safe and feasible for palliative ablation of locally advanced prostate cancer. The therapy seems to accomplish long-term hematuria control, can relieve bladder outlet obstruction in selected patients, and seems to reduce the burden of hospitalization due to local complications. Trial Registration Number: NCT03350529.

Feasibility of MRI-guided transurethral ultrasound for lesion-targeted ablation of prostate cancer.

Background: MRI-guided transurethral ultrasound ablation (TULSA) has been evaluated for organ-confined prostate cancer (PCa). The purpose of this study was to assess the safety and toxicity, accuracy and short-term evolution of cell-death after lesion-targeted TULSA.Methods: This prospective, registered, Phase-I treat-and-3-week-resect-study enrolled six patients with MRI-visible-biopsy-concordant PCa. Lesions were targeted using TULSA with radical intent, except near neurovascular bundles (NVB). Robot-assisted-laparoscopic-prostatectomy (RALP) was performed at 3 weeks. Post-TULSA assessments included MRI (1 and 3 weeks), adverse events and quality-of-life (QoL) to 3 weeks, followed by RALP and whole-mount-histology. Treatment accuracy and demarcation of thermal injury were assessed using MRI and histology.Results: Six patients (median age = 70 years, prostate volume = 60 ml, PSA = 8.9 ng/ml) with eight biopsy-confirmed MRI-lesions (PIRADS ≥3) were TULSA-treated without complications (median sonication and MRI-times of 17 and 117 min). Foley-catheter removal was uneventful at 2-3 days. Compared to baseline, no differences in QoL were noted at 3 weeks. During follow-up, MRI-derived non-perfused-volume covered ablated targets and increased 36% by 3 weeks, correlating with necrosis-area on histology. Mean histological demarcation between complete necrosis and outer-limit-of-thermal-injury was 1.7 ± 0.4 mm. Coagulation necrosis extended to capsule except near NVB, where 3 mm safety-margins were applied. RALPs were uncomplicated and histopathology showed no viable cancer within the ablated tumor-containing target.Conclusions: Lesion-targeted TULSA demonstrates accurate and safe ablation of PCa. A significant increase of post-TULSA non-perfused-volume was observed during 3 weeks follow-up concordant with necrosis on histology. TULSA achieved coagulation necrosis of all targeted tissues. A limitation of this treat-and-resect-study-design was conservative treatment near NVB in patients scheduled for RALP.

Transurethral ultrasound therapy of the prostate in the presence of calcifications: A simulation study.

PURPOSE: Transurethral ultrasound therapy is an investigational treatment modality which could potentially be used for the localized treatment of prostate cancer. One of the limiting factors of this therapy is prostatic calcifications. These attenuate and reflect ultrasound and thus reduce the efficacy of the heating. The aim of this study is to investigate how prostatic calcifications affect therapeutic efficacy, and to identify the best sonication strategy when calcifications are present. METHODS: Realistic computational models were used on clinical patient data in order to simulate different therapeutic situations with naturally occurring calcifications as well as artificial calcifications of different sizes (1-10 mm) and distances (5-15 mm). Furthermore, different sonication strategies were tested in order to deliver therapy to the untreated tissue regions behind the calcifications. RESULTS: The presence of calcifications in front of the ultrasound field was found to increase the peak pressure by 100% on average while the maximum temperature only rose by 9% during a 20-s sonication. Losses in ultrasound energy were due to the relatively large acoustic impedance mismatch between the prostate tissue and the calcifications (1.63 vs 3.20 MRayl) and high attenuation coefficient (0.78 vs 2.64 dB/MHz1.1 /cm), which together left untreated tissue regions behind the calcifications. In addition, elevated temperatures were seen in the region between the transducer and the calcifications. Lower sonication frequencies (1-4 MHz) were not able to penetrate through the calcifications effectively, but longer sonication durations (20-60 s) with selective transducer elements were effective in treating the tissue regions behind the calcifications. CONCLUSIONS: Prostatic calcifications limit the reach of therapeutic ultrasound treatment due to reflections and attenuation. The tissue regions behind the calcifications can possibly be treated using longer sonication durations combined with proper transducer element selection. However, caution should be taken with calcifications located close to sensitive organs such as the urethra, bladder neck, or rectal wall.