Diffusion-weighted MRI with deep learning for visualizing treatment results of MR-guided HIFU ablation of uterine fibroids.

OBJECTIVES: No method is available to determine the non-perfused volume (NPV) repeatedly during magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations of uterine fibroids, as repeated acquisition of contrast-enhanced T1-weighted (CE-T1w) scans is inhibited by safety concerns. The objective of this study was to develop and test a deep learning-based method for translation of diffusion-weighted imaging (DWI) into synthetic CE-T1w scans, for monitoring MR-HIFU treatment progression. METHODS: The algorithm was retrospectively trained and validated on data from 33 and 20 patients respectively who underwent an MR-HIFU treatment of uterine fibroids between June 2017 and January 2019. Postablation synthetic CE-T1w images were generated by a deep learning network trained on paired DWI and reference CE-T1w scans acquired during the treatment procedure. Quantitative analysis included calculation of the Dice coefficient of NPVs delineated on synthetic and reference CE-T1w scans. Four MR-HIFU radiologists assessed the outcome of MR-HIFU treatments and NPV ratio based on the synthetic and reference CE-T1w scans. RESULTS: Dice coefficient of NPVs was 71% (± 22%). The mean difference in NPV ratio was 1.4% (± 22%) and not statistically significant (p = 0.79). Absolute agreement of the radiologists on technical treatment success on synthetic and reference CE-T1w scans was 83%. NPV ratio estimations on synthetic and reference CE-T1w scans were not significantly different (p = 0.27). CONCLUSIONS: Deep learning-based synthetic CE-T1w scans derived from intraprocedural DWI allow gadolinium-free visualization of the predicted NPV, and can potentially be used for repeated gadolinium-free monitoring of treatment progression during MR-HIFU therapy for uterine fibroids. KEY POINTS: • Synthetic CE-T1w scans can be derived from diffusion-weighted imaging using deep learning. • Synthetic CE-T1w scans may be used for visualization of the NPV without using a contrast agent directly after MR-HIFU ablations of uterine fibroids.

Magnetic Resonance Imaging-targeted Prostate Biopsy Compared with Systematic Prostate Biopsy in Biopsy-naïve Patients with Suspected Prostate Cancer.

Background: It remains uncertain whether transrectal ultrasound (TRUS)-guided systematic biopsies can be omitted and rely solely on multiparametric magnetic resonance imaging-targeted biopsies (MRI-TBx) in biopsy-naïve men suspected of prostate cancer (PCa). Objective: To compare PCa detection in biopsy-naïve men between systematic biopsy and MRI-TBx. Design setting and participants: A prospective cohort study was conducted in a Dutch teaching hospital. Consecutive patients with suspected PCa, no history of biopsy, and no clinical suspicion of metastasis underwent both TRUS-guided systematic biopsies and MRI-TBx by multiparametric magnetic resonance imaging (mpMRI)-ultrasound fusion, including sham biopsies in case of negative mpMRI. Outcome measurements and statistical analysis: Clinically significant PCa (csPCa), defined as group ≥2 on the International Society of Urological Pathology grading, was detected. Results and limitations: The overall prevalence of csPCa, irrespective of biopsy technique, was 37.4% (132/353) in our population. MRI-TBx were performed in 263/353 (74.5%) patients with suspicious mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3). The detection rates for csPCa were 39.5% for MRI-TBx and 42.9% for systematic biopsies. The added values, defined as the additional percentages of patients with csPCa detected by adding one biopsy technique, were 8.7% for the systematic biopsies and 5.3% for MRI-TBx. In patients with nonsuspicious mpMRI, five cases (6%) of csPCa were found by systematic biopsies. Conclusions: This study in biopsy-naïve patients suspected for PCa showed that systematic biopsies have added value to MRI-TBx alone in patients with mpMRI PI-RADS >2. Patient summary: We studied magnetic resonance imaging (MRI)-guided prostate biopsy for diagnosing prostate cancer and compared it with the standard method of prostate biopsy. Standard systematic biopsies cannot be omitted in patients with suspicious MRI, as they add to the detection of significant prostate cancer.

Increased MR-guided high intensity focused ultrasound (MR-HIFU) sonication efficiency of uterine fibroids after carbetocin administration.

Purpose: We investigated whether administration of the long-acting uterus stimulant carbetocin increased intra-subject sonication efficiency during Magnetic Resonance image guided High Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids. Method: In this prospective cohort study, thirty women with symptomatic uterine fibroids undergoing MR-HIFU treatment were included between January 2018 and January 2019. Treatment started with three sonications on one side of the uterine fibroid. Subsequently, one ampoule of 1 mL carbetocin (100 µg/mL) was administered intravenously and treatment continued with three sonications on the other side of the uterine fibroid. We compared the intra-subject sonication efficiency, in terms of Energy Efficiency Factor (EEF), thermal dose volume and sonication time to ablate one cm3 of fibroid tissue, before and after carbetocin administration. Adverse events that occurred within 30 min after carbetocin administration were recorded. Results: Sonication efficiency improved after carbetocin administration as indicated by a significant decrease in EEF and sonication time (p = 0.006 and p = 0.001 respectively), and a significant increase in thermal dose volume reached (p = <0.001). Five women (16.7%) experienced temporary tachycardia, one women in combination with headache, within 30 min after carbetocin administration. Conclusion: Administration of the long-acting uterus stimulant carbetocin improved the MR-HIFU treatment intra-subject sonication efficiency in women with symptomatic uterine fibroids.

Combining radiotherapy and focused ultrasound for pain palliation of cancer induced bone pain; a stage I/IIa study according to the IDEAL framework.

BACKGROUND: Cancer induced bone pain (CIBP) strongly interferes with patient's quality of life. Currently, the standard of care includes external beam radiotherapy (EBRT), resulting in pain relief in approximately 60% of patients. Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) is a promising treatment modality for CIBP. METHODS: A single arm, R-IDEAL stage I/IIa study was conducted. Patients presenting at the department of radiation oncology with symptomatic bone metastases in the appendicular skeleton, as well as in the sacrum and sternum were eligible for inclusion. All participants underwent EBRT, followed by MR-HIFU within 4 days. Safety and feasibility were assessed, and pain scores were monitored for 4 weeks after completing the combined treatment. RESULTS: Six patients were enrolled. Median age was 67 years, median lesion diameter was 56,5 mm. In all patients it was logistically possible to plan and perform the MR-HIFU treatment within 4 days after EBRT. All patients tolerated the combined procedure well. Pain response was reported by 5 out of 6 patients at 7 days after completion of the combined treatment, and stabilized on 60% at 4 weeks follow up. No treatment related serious adverse events occurred. CONCLUSION: This is the first study to combine EBRT with MR-HIFU. Our results show that combined EBRT and MR-HIFU in first-line treatment of CIBP is safe and feasible, and is well tolerated by patients. Superiority over standard EBRT, in terms of (time to) pain relief and quality of life need to be evaluated in comparative (randomized) study.

Development and clinical evaluation of a 3-step modified manipulation protocol for MRI-guided high-intensity focused ultrasound of uterine fibroids.

OBJECTIVES: The clinical applicability of magnetic resonance image-guided high-intensity focused ultrasound (MR-HIFU) treatment of uterine fibroids is often limited due to inaccessible fibroids or bowel interference. The aim of this study was to implement a newly developed 3-step modified manipulation protocol and to evaluate its influence on the number of eligible women and treatment failure rate. METHODS: From June 2016 to June 2018, 165 women underwent a screening MRI examination, 67 women of whom were consecutively treated with MR-HIFU at our institution. Group 1 (n = 20) was treated with the BRB manipulation protocol which consisted of sequential applications of urinary bladder filling, rectal filling, and urinary bladder emptying. Group 2 (n = 47) was treated using the 3-step modified manipulation protocol which included (1) the BRB maneuver with adjusted rectal filling by adding psyllium fibers to the solution; (2) Trendelenburg position combined with bowel massage; (3) the manual uterine manipulation (MUM) method for uterine repositioning. A comparison was made between the two manipulation protocols to evaluate differences in safety, the eligibility percentage, and treatment failure rate due to unsuccessful manipulation. RESULTS: After implementing the 3-step modified manipulation protocol, our ineligibility rate due to bowel interference or inaccessible fibroids decreased from 18% (16/88) to 0% (0/77). Our treatment failure rate due to unsuccessful manipulation decreased from 20% (4/20) to 2% (1/47). There were no thermal complications to the bowel or uterus. CONCLUSIONS: Implementation of the 3-step modified manipulation protocol during MR-HIFU therapy of uterine fibroids improved the eligibility percentage and reduced the treatment failure rate. TRIAL REGISTRATION: Registry number NL56182.075.16 KEY POINTS: • A newly developed 3-step modified manipulation protocol was successfully implemented without the occurrence of thermal complication to the bowel or uterus. • The 3-step modified manipulation protocol increased our eligibility percentage for MR-HIFU treatment of uterine fibroids. • The 3-step modified manipulation protocol reduced our treatment failure rate for MR-HIFU treatment of uterine fibroids.

Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium.

BACKGROUND: Reactive oxygen species (ROS) released from activated polymorphonuclear leukocytes (PMN) during surgery may play a crucial role in the enhanced distant tumor recurrence after surgical trauma. MATERIALS AND METHODS: The effect of PMN on the adhesion of the human colon carcinoma cells HT29, Caco2 and the pancreatic carcinoma cells PanC1 and BxPC3 to microvascular endothelium (MEC) was studied in a reproducible human in vitro model. RESULTS: Pre-incubation of MEC with tissue plasminogen activator (TPA)-activated PMN resulted in more than 200% increase of tumor cell adhesion to MEC compared to control (p < 0.01). Exposure of MEC to TPA or non-activated PMN did not significantly affect adhesion. Addition of the antioxidant enzymes superoxide dismutase or catalase significantly decreased tumor cell adhesion to MEC exposed to PMN. CONCLUSION: These results demonstrate that activated PMN promote tumor cell adhesion to the microvascular wall by production of ROS. This indicates that in tackling the ROS production, preventing tumor recurrence at distant sites, might be feasible.

The influence of reactive oxygen species on the adhesion of pancreatic carcinoma cells to the peritoneum.

Postoperative peritoneal carcinomatosis is a significant clinical problem after "curative" resection of pancreatic carcinoma. Preoperative surgical trauma activates a cascade of peritoneal defense mechanisms responsible for postoperative intra-abdominal tumor recurrence. Reactive oxygen species (ROS) play a pivotal role in this postoperative inflammatory reaction. This study explores the influence of ROS on adhesion of human pancreatic carcinoma cells to human mesothelial cells. Furthermore this study explores the influence of ROS on the presentation of adhesion molecules on Panc-1 and mesothelial cells. ROS were produced using the enzymatic reaction of xanthine with xanthine oxidase (X/XO). A reproducible in vitro assay to study adhesion of human Panc-1 carcinoma tumor cells to a mesothelial cell monolayer of primary human mesothelial cells was used. Mesothelial monolayers were incubated with ROS produced prior to adhesion of the tumor cells. Incubation of the mesothelial cells with X/XO resulted in a significant increase (69.5%) in adhesion of Panc-1 in all patients. SOD/catalase, anti-oxidants, could reduce this increase by 56.7%. ROS significantly influenced the expression of the adhesion molecules ICAM-1, VCAM-1 and CD44h on mesothelial cells, but did not influence adhesion molecule expression on Panc-1. The ROS released during the post-operative inflammatory reaction may play an important role in the adhesion of pancreatic tumor cells to the mesothelium-possibly by influencing adhesion molecule expression on mesothelial cells. Therefore ROS can partly be responsible for the enhanced post-operative intra-abdominal tumor recurrence.

Pro-inflammatory cytokines affect pancreatic carcinoma cell. Endothelial cell interactions.

OBJECTIVES: The potential role of surgery-induced pro-inflammatory cytokines on the development of tumor recurrence in pancreatic cancer was investigated. MAIN OUTCOME MEASURES: The adhesion of 3 human pancreatic carcinoma cell lines, PanC1, MiaPaCa and BxPC3 to monolayers of microvascular endothelial cells after pre-incubation with 0.1 or 10 ng/mL IL-1beta, TNF-alpha or IL-6 was assessed in a reproducible human in vitro assay. Untreated monolayers served as controls. RESULTS: Pre-incubation of microvascular endothelial cells with IL-1beta or TNF-alpha, but not IL-6, increased adhesion of all three tumor cell lines as compared to adhesion in the control group. Maximally stimulated adhesion for PanC1 reached 159%, for MiaPaCa 204% and for BxPC3 155% (all vs. the control, P<0.001). Pre-incubation of microvascular endothelial cells with IL-1beta or TNF-alpha resulted in a significant up-regulation of E-selectin, ICAM-1 and VCAM-1 expression. The addition of anti-E-selectin, anti-ICAM-1 or anti-VCAM-1 monoclonal antibodies did not decrease adhesion to microvascular endothelial cells pre-incubated with IL-1beta. Therefore, enhanced tumor cell binding seems to be independent of these adhesion molecules. CONCLUSIONS: Pro-inflammatory cytokines derived from surgical trauma may enhance tumor cell adhesion to microvascular endothelial cells and thus bring about more successful tumor cell implantation resulting in an increased risk of metastasis formation.

Influence of proinflammatory cytokines on the adhesion of human colon carcinoma cells to lung microvascular endothelium.

In this experimental study, the influence of surgery-induced proinflammatory cytokines on tumor recurrence in the lung was investigated. A reproducible human in vitro assay was developed to study the adhesion of HT29 colon carcinoma cells to monolayers of microvascular endothelial cells of the lung (HMVECs-L) or human umbilical venous endothelial cells (HUVECs). Preincubation of HMVECs-L with maximally active concentrations of IL-1beta and TNF-alpha, but not with IL-6, resulted in at least 250% adhesion compared to control adhesion (p