Uri Lindner | The Hebrew University of Jerusalem (original) (raw)

Papers by Uri Lindner

The Journal of Urology, Apr 1, 2016

treatment resistance in castrate resistant prostate cancer continues to remain a clinical problem... more treatment resistance in castrate resistant prostate cancer continues to remain a clinical problem. Co-targeting approaches are of significant interest to slow the progression of disease and delay the onset of resistance. With both Akt and MEK pathways becoming activated as prostate cancer develops resistance to AR-targeted therapy, this study explores co-targeting these pathways in AR positive prostate cancer models. METHODS: Using in vitro models of prostate cancer progression from androgen dependent to castrate resistant and ENZ-resistant disease, we evaluated the effect of Akt and/or MEK inhibition with AZD5363 and PD0325901, respectively, on cell proliferation, apoptosis and downstream signalling pathways. For in vivo models, we tested the combination of Akt and MEK inhibition on xenografts in castrated mice using MR49F or 22RV1 cells which are resistant to ENZ. RESULTS: Inhibition of Akt reduced S6 phosphorylation, inhibited growth and induced apoptosis in LNCaP-derived cells; the addition of a MEK inhibitor increased apoptosis and cell cycle arrest, but did not further decrease cell proliferation. In contrast, PTEN wild-type 22RV1 cells demonstrated a greater sensitivity to MEK inhibition, but were generally insensitive to Akt inhibition. In vivo, combination of Akt and MEK inhibition resulted in more consistent tumour growth inhibition of MR49F xenografts and longer disease specific survival than Akt inhibitor monotherapy, with induction of pERK staining being evident in some AZD5363 monotherapy treated tumours. Conversely, 22RV1 xenografts had greater resistance to Akt inhibition and greater sensitivity to MEK inhibition. CONCLUSIONS: Our data suggest that combination of Akt and MEK inhibition may improve prostate cancer control in ENZ-resistant prostate cancer. Further, with the major effect in both MR49F and 22RV1 xenografts attributable to one inhibitor, our results also suggest the importance of characterizing the dominant oncogenic pathway in each patient's tumour in order to select optimal therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Dec 18, 2010

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Mar 16, 2012

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 23, 2012

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, May 4, 2012

Cancer Immunology Research, 2016

Vascular-targeted photodynamic therapy with WST11 (VTP) enables safe and efficient non-thermal ab... more Vascular-targeted photodynamic therapy with WST11 (VTP) enables safe and efficient non-thermal ablation of solid tumors as demonstrated by recent phase II and III clinical trials with localized prostate cancer. Studies in animal models in our labs revealed that VTP of immunogenic tumors elicits innate/adaptive immune responses and over 80% cures with consequent long-lasting anti-tumor protection. Here we show that local VTP combined with immune modulation in rodents, bearing weakly immunogenic prostate and triple negative breast tumors, results in eradication of remote metastases and animal cure. Methodology: 4T1-luc cells were subcutaneously grafted at the hind leg of Balb/C mice. Colony forming assay confirmed tumor cell spreading to the lungs already by day 7 post grafting when local VTP was delivered to the primary tumor. The study comprised: (i) animals treated by VTP alone or (ii) following 50mg/kg cyclophosphamide (CTX) on day 4 post grafting, or (iii) VTP combined with anti-...

Nature Reviews Urology, Sep 27, 2016

Globally, the increased uptake of serum PSA level screening led to an increase in the number of d... more Globally, the increased uptake of serum PSA level screening led to an increase in the number of diagnoses of low-risk and intermediate-risk prostate cancer. Traditionally, these patients have been considered for either active surveillance programmes or radical whole-gland therapies, such as prostatectomy or radiotherapy. Focal therapy is an emerging treatment option that involves the focal ablation of prostate cancer with preservation of surrounding healthy tissue. This approach might result in reduced morbidity when compared with whole-gland therapies. In current practice, much controversy surrounds optimal patient selection and preoperative tumour localization strategies. Focal therapy modalities include cryotherapy, high-intensity focused ultrasound, laser ablation, photodynamic therapy, irreversible electroporation, radiofrequency ablation and focal brachytherapy. However, as long-term oncological data for focal therapies are lacking, formal recommendations for its use cannot be made.

Magnetic Resonance in Medicine, Jun 25, 2013

Purpose: A critical requirement of MR-guided interventions is the visualization of an instrument ... more Purpose: A critical requirement of MR-guided interventions is the visualization of an instrument (e.g., catheter, needle) during the procedure. One approach is to fill the instrument with a contrast agent. Previously, the optimization of contrast agent visualization was performed only empirically. In the present study, an analytic optimization of contrast agent SNR efficiency was performed for a spoiled gradient echo pulse sequence. Methods: Optimal flip angle, repetition time, echo time, and contrast agent concentration were derived analytically. The solution is valid for any contrast agent, provided the relationship between T 1 , T 2 , and doping concentration is known. Results: Phantom experiments validated the analytic optimization for Gd-and MnCl 2-based contrast agents. Results showed excellent agreement between experimentally predicted and theoretically observed magnetization behavior. In vivo experiments demonstrated optimized contrast agent visualization in brain, heart, and prostate applications. The results demonstrated the large SNR that can be achieved with analytic optimization. As a practical guideline, an 11% dilution of 500 mMol/L Gd-DTPA solution, repetition time % 4 ms, echo time % 1 ms, and h % 65 was found to provide a large SNR. Conclusion: This study derived and validated a method for analytically optimizing contrast agent SNR efficiency. This information may be useful for visualizing instruments during MR-guided interventions.

Medical Physics, Jan 4, 2013

Purpose:To demonstrate the capabilities of a new magnetic resonance imaging (MRI)‐guided system f... more Purpose:To demonstrate the capabilities of a new magnetic resonance imaging (MRI)‐guided system for delivering needles to the prostate for focal therapy. Included is a presentation of the design of the system and its user interface, evaluation of MR‐compatibility, and quantitative evaluation of guidance accuracy and repeatability within the bore of a clinical MRI scanner.Methods:The use of MRI for visualization of tumors, intraoperative visualization of interventional tools, and thermometry for controlled ablation of lesions is becoming increasingly prevalent. In this work, the authors present a prototype system for guiding needles to prostate tumors within the bore of an MRI scanner for use in focal laser thermal ablation of prostate tumors. The system consists of a manually actuated trajectory alignment device that allows a physician to precisely align a set of needle guides with an intended target in the prostate within the bore of a clinical closed‐bore MRI scanner. Needle insertion is then performed transperineally, with the patient in the bore of the MRI, and custom software provides monitoring of thermal ablative procedures.Results:The system is shown to have a minimal effect on image distortion, and only a 6% decrease in image signal‐to‐noise ratio. Through needle insertion tests in tissue‐mimicking phantoms, the system's potential for reliably guiding needles to intra‐MR targets within 2.64 mm has been demonstrated. Use of the system to deliver focal laser ablation therapy to two patients showed that it can be used to deliver needles with minimal disruption of workflow, and in less time than when insertions are performed freehand or with a fixed grid template.Conclusions:A system for delivering needles to a patient's prostate for focal therapy within the bore of an MRI scanner has been developed. Results from needle insertion tests in phantoms suggest that the system has the potential to provide accurate delivery of focal therapy to prostate tumors of the smallest clinically significant size. Initial tests in two patients showed that needle deflection was larger than in phantoms, but methods of manually compensating for this effect were employed and needles were delivered to treatment sites with sufficient accuracy to deliver effective treatment. In addition, the treatment was delivered in less time than with a fixed grid template or freehand insertions. Despite this success, methods of reducing needle deflection are needed in order to fully utilize the potential of this system, and further reduce total procedure time.

The Journal of Urology, Oct 1, 2009

We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for... more We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Proceedings of SPIE, Mar 12, 2014

ABSTRACT Focal therapy of localized prostate cancer is receiving increased attention due to its p... more ABSTRACT Focal therapy of localized prostate cancer is receiving increased attention due to its potential for providing effective cancer control in select patients with minimal treatment-related side effects. Magnetic resonance imaging (MRI)-guided focal laser ablation (FLA) therapy is an attractive modality for such an approach. In FLA therapy, accurate placement of laser fibers is critical to ensuring that the full target volume is ablated. In practice, error in needle placement is invariably present due to pre- to intra-procedure image registration error, needle deflection, prostate motion, and variability in interventionalist skill. In addition, some of these sources of error are difficult to control, since the available workspace and patient positions are restricted within a clinical MRI bore. In an attempt to take full advantage of the utility of intraprocedure MRI, while minimizing error in needle placement, we developed an MRI-compatible mechatronic system for guiding needles to the prostate for FLA therapy. The system has been used to place interstitial catheters for MRI-guided FLA therapy in eight subjects in an ongoing Phase I/II clinical trial. Data from these cases has provided quantification of the level of uncertainty in needle placement error. To relate needle placement error to clinical outcome, we developed a model for predicting the probability of achieving complete focal target ablation for a family of parameterized treatment plans. Results from this work have enabled the specification of evidence-based selection criteria for the maximum target size that can be confidently ablated using this technique, and quantify the benefit that may be gained with improvements in needle placement accuracy.

Canadian Urological Association journal, May 1, 2013

European Radiology, Apr 25, 2018

Objectives To evaluate the feasibility and safety of focal therapy for low-intermediate risk pros... more Objectives To evaluate the feasibility and safety of focal therapy for low-intermediate risk prostate cancer (PCa) with magnetic resonance-guided high frequency focused ultrasound (MRgFUS) Methods This IRB-approved phase 1 prospective study enrolled eight patients with prostate specific antigen (PSA) ≤ 10 ng/ml, ≤ cT2a and Gleason score ≤ 7 (4 + 3) disease following informed consent. Under MRI guidance, focused high frequency ultrasound energy was delivered to ablate the target tissue. Treatment-related adverse events were recorded. Oncologic outcomes were evaluated with multiparametric MRI, PSA and TRUS biopsy at 6 months following treatment. Results Ten target lesions [six Gleason 6 lesions, two Gleason 7 (3 + 4) and two Gleason 7 (4 + 3)] were treated in eight men (prostate volume range, 25-50 cc; mean MRI time, 248 min per patient; mean sonication duration, 65 min). Mean target volume was 2.7 cc and mean post-treatment non-perfused volume was 4.3 cc. Quality of life parameters were similar between baseline and 6 months in 6/8 patients. All treated regions were negative on MRI; 4/8 patients and 6/10 target lesions (60%) were clear of disease on biopsy. One patient with 2-mm Gleason 8 disease in one of five cores from treatment site (4 + 3 disease at baseline) subsequently underwent prostatectomy with negative surgical margins. Three patients with low volume (5-15%) Gleason 6 residual disease were offered active surveillance. Mean PSA decreased from 5.06 at baseline to 3.4 ng/ml at 6 months. Conclusion MRgFUS is a feasible and safe method of noninvasively ablating low-intermediate risk PCa with acceptable shortterm oncologic outcomes. Key Points • Focal therapy selectively ablates locally confined, clinically significant index lesion with a margin while sparing rest of gland and adjacent vital structures. • Magnetic resonance-guided focused high frequency ultrasound surgery (MRgFUS) combines MRI with HIFU. • MRgFUS provides ability to monitor treatments in real time and allows a targeted approach for focal ablation. • MRgFUS is a feasible, safe method of noninvasively ablating low-intermediate risk PCa. • MRgFUS provides acceptable oncologic outcomes at 6 months.

The Journal of Urology, Apr 1, 2009

Results: The robot is fully operational within a closed bore MRI system. The ultrasonic motors le... more Results: The robot is fully operational within a closed bore MRI system. The ultrasonic motors lend to compact design (width 30 cm) that allows for trans-perineal prostatic procedures within the closed bore of a high resolution MRI device. To date, all testing was ...

Future Oncology, Jun 1, 2011

Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in ... more Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in oncology. For example, partial nephrectomy is now accepted as a preferred alternative over radical nephrectomy for small (up to 4 cm or T1) tumors. Focal therapy (FT) is another organ-preserving strategy applying energy (cryotherapy, laser ablation and/or high-intensity focused ultrasound) to destroy tumors while leaving the majority of the organ, surrounding tissue and structures unscathed and functional. Owing to the perceived multifocality of prostate cancer (PCa) technology limitations, in the past PCa was not considered suitable for FT. However, with the rise of active surveillance for the management of low-risk PCa in carefully selected patients, FT is emerging as an alternative. This is owing to technology improvements in imaging and energy-delivery systems to ablate tissue, as well as the realization that many men and clinicians still desire tumor control. With the postulated ability to ablate tumors with minimal morbidity, FT may have found a role in the management of PCa; the aim of FT a being long-term cancer control without the morbidity associated with radical therapies. Data for FT in PCa have been derived from case series and small Phase I trials, with larger cohort studies with longer followup having only just commenced. More data from large trials on the safety and efficacy of FT are required before this approach can be recommended in men with PCa. Importantly, studies must confirm that no viable cancer cells remain in the region of ablation. FT might eventually prove to be a 'middle ground' between active surveillance and radical treatment, combining minimal morbidity with cancer control and the potential for retreatment. Keywords n active surveillance n cryotherapy n focal therapy n HIFU n laser n MRI n prostate cancer

European Urology Supplements, Feb 1, 2012

Lecture Notes in Computer Science, 2012

We present a device that has been developed for delivering prostate focal thermal therapy under m... more We present a device that has been developed for delivering prostate focal thermal therapy under magnetic resonance imaging (MRI) guidance. Unlike most existing devices, ours is capable of delivering needles to targets in the prostate without removing the patient from the scanner. This feature greatly reduces procedure time and increases accuracy. The device consists of a mechanical linkage encoded with optical incremental encoders, and is manually actuated. A custom magnetic resonance (MR) compatible alignment interface allows the user to manually align the device to its target with high accuracy inbore in very short time. The use of manual actuation over motors greatly reduces the complexity and bulk of the system, making it much more compact and portable. This is important when dealing with such tight space constraints. Needle targeting experiments in gel phantoms have demonstrated the device's ability to deliver needles with an accuracy of 2.1 +/-1.3 mm.

F1000 Medicine Reports, Dec 8, 2010

This concise review attempts to highlight the recent advances in magnetic resonance imaging (MRI)... more This concise review attempts to highlight the recent advances in magnetic resonance imaging (MRI) in relation to all the different aspects of prostate cancer (PCa), and outlines future implications of MRI in the diagnosis, treatment, and surveillance of PCa.

The Journal of Urology, Apr 1, 2016

treatment resistance in castrate resistant prostate cancer continues to remain a clinical problem... more treatment resistance in castrate resistant prostate cancer continues to remain a clinical problem. Co-targeting approaches are of significant interest to slow the progression of disease and delay the onset of resistance. With both Akt and MEK pathways becoming activated as prostate cancer develops resistance to AR-targeted therapy, this study explores co-targeting these pathways in AR positive prostate cancer models. METHODS: Using in vitro models of prostate cancer progression from androgen dependent to castrate resistant and ENZ-resistant disease, we evaluated the effect of Akt and/or MEK inhibition with AZD5363 and PD0325901, respectively, on cell proliferation, apoptosis and downstream signalling pathways. For in vivo models, we tested the combination of Akt and MEK inhibition on xenografts in castrated mice using MR49F or 22RV1 cells which are resistant to ENZ. RESULTS: Inhibition of Akt reduced S6 phosphorylation, inhibited growth and induced apoptosis in LNCaP-derived cells; the addition of a MEK inhibitor increased apoptosis and cell cycle arrest, but did not further decrease cell proliferation. In contrast, PTEN wild-type 22RV1 cells demonstrated a greater sensitivity to MEK inhibition, but were generally insensitive to Akt inhibition. In vivo, combination of Akt and MEK inhibition resulted in more consistent tumour growth inhibition of MR49F xenografts and longer disease specific survival than Akt inhibitor monotherapy, with induction of pERK staining being evident in some AZD5363 monotherapy treated tumours. Conversely, 22RV1 xenografts had greater resistance to Akt inhibition and greater sensitivity to MEK inhibition. CONCLUSIONS: Our data suggest that combination of Akt and MEK inhibition may improve prostate cancer control in ENZ-resistant prostate cancer. Further, with the major effect in both MR49F and 22RV1 xenografts attributable to one inhibitor, our results also suggest the importance of characterizing the dominant oncogenic pathway in each patient's tumour in order to select optimal therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Dec 18, 2010

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Mar 16, 2012

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Nov 23, 2012

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, May 4, 2012

Cancer Immunology Research, 2016

Vascular-targeted photodynamic therapy with WST11 (VTP) enables safe and efficient non-thermal ab... more Vascular-targeted photodynamic therapy with WST11 (VTP) enables safe and efficient non-thermal ablation of solid tumors as demonstrated by recent phase II and III clinical trials with localized prostate cancer. Studies in animal models in our labs revealed that VTP of immunogenic tumors elicits innate/adaptive immune responses and over 80% cures with consequent long-lasting anti-tumor protection. Here we show that local VTP combined with immune modulation in rodents, bearing weakly immunogenic prostate and triple negative breast tumors, results in eradication of remote metastases and animal cure. Methodology: 4T1-luc cells were subcutaneously grafted at the hind leg of Balb/C mice. Colony forming assay confirmed tumor cell spreading to the lungs already by day 7 post grafting when local VTP was delivered to the primary tumor. The study comprised: (i) animals treated by VTP alone or (ii) following 50mg/kg cyclophosphamide (CTX) on day 4 post grafting, or (iii) VTP combined with anti-...

Nature Reviews Urology, Sep 27, 2016

Globally, the increased uptake of serum PSA level screening led to an increase in the number of d... more Globally, the increased uptake of serum PSA level screening led to an increase in the number of diagnoses of low-risk and intermediate-risk prostate cancer. Traditionally, these patients have been considered for either active surveillance programmes or radical whole-gland therapies, such as prostatectomy or radiotherapy. Focal therapy is an emerging treatment option that involves the focal ablation of prostate cancer with preservation of surrounding healthy tissue. This approach might result in reduced morbidity when compared with whole-gland therapies. In current practice, much controversy surrounds optimal patient selection and preoperative tumour localization strategies. Focal therapy modalities include cryotherapy, high-intensity focused ultrasound, laser ablation, photodynamic therapy, irreversible electroporation, radiofrequency ablation and focal brachytherapy. However, as long-term oncological data for focal therapies are lacking, formal recommendations for its use cannot be made.

Magnetic Resonance in Medicine, Jun 25, 2013

Purpose: A critical requirement of MR-guided interventions is the visualization of an instrument ... more Purpose: A critical requirement of MR-guided interventions is the visualization of an instrument (e.g., catheter, needle) during the procedure. One approach is to fill the instrument with a contrast agent. Previously, the optimization of contrast agent visualization was performed only empirically. In the present study, an analytic optimization of contrast agent SNR efficiency was performed for a spoiled gradient echo pulse sequence. Methods: Optimal flip angle, repetition time, echo time, and contrast agent concentration were derived analytically. The solution is valid for any contrast agent, provided the relationship between T 1 , T 2 , and doping concentration is known. Results: Phantom experiments validated the analytic optimization for Gd-and MnCl 2-based contrast agents. Results showed excellent agreement between experimentally predicted and theoretically observed magnetization behavior. In vivo experiments demonstrated optimized contrast agent visualization in brain, heart, and prostate applications. The results demonstrated the large SNR that can be achieved with analytic optimization. As a practical guideline, an 11% dilution of 500 mMol/L Gd-DTPA solution, repetition time % 4 ms, echo time % 1 ms, and h % 65 was found to provide a large SNR. Conclusion: This study derived and validated a method for analytically optimizing contrast agent SNR efficiency. This information may be useful for visualizing instruments during MR-guided interventions.

Medical Physics, Jan 4, 2013

Purpose:To demonstrate the capabilities of a new magnetic resonance imaging (MRI)‐guided system f... more Purpose:To demonstrate the capabilities of a new magnetic resonance imaging (MRI)‐guided system for delivering needles to the prostate for focal therapy. Included is a presentation of the design of the system and its user interface, evaluation of MR‐compatibility, and quantitative evaluation of guidance accuracy and repeatability within the bore of a clinical MRI scanner.Methods:The use of MRI for visualization of tumors, intraoperative visualization of interventional tools, and thermometry for controlled ablation of lesions is becoming increasingly prevalent. In this work, the authors present a prototype system for guiding needles to prostate tumors within the bore of an MRI scanner for use in focal laser thermal ablation of prostate tumors. The system consists of a manually actuated trajectory alignment device that allows a physician to precisely align a set of needle guides with an intended target in the prostate within the bore of a clinical closed‐bore MRI scanner. Needle insertion is then performed transperineally, with the patient in the bore of the MRI, and custom software provides monitoring of thermal ablative procedures.Results:The system is shown to have a minimal effect on image distortion, and only a 6% decrease in image signal‐to‐noise ratio. Through needle insertion tests in tissue‐mimicking phantoms, the system's potential for reliably guiding needles to intra‐MR targets within 2.64 mm has been demonstrated. Use of the system to deliver focal laser ablation therapy to two patients showed that it can be used to deliver needles with minimal disruption of workflow, and in less time than when insertions are performed freehand or with a fixed grid template.Conclusions:A system for delivering needles to a patient's prostate for focal therapy within the bore of an MRI scanner has been developed. Results from needle insertion tests in phantoms suggest that the system has the potential to provide accurate delivery of focal therapy to prostate tumors of the smallest clinically significant size. Initial tests in two patients showed that needle deflection was larger than in phantoms, but methods of manually compensating for this effect were employed and needles were delivered to treatment sites with sufficient accuracy to deliver effective treatment. In addition, the treatment was delivered in less time than with a fixed grid template or freehand insertions. Despite this success, methods of reducing needle deflection are needed in order to fully utilize the potential of this system, and further reduce total procedure time.

The Journal of Urology, Oct 1, 2009

We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for... more We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Proceedings of SPIE, Mar 12, 2014

ABSTRACT Focal therapy of localized prostate cancer is receiving increased attention due to its p... more ABSTRACT Focal therapy of localized prostate cancer is receiving increased attention due to its potential for providing effective cancer control in select patients with minimal treatment-related side effects. Magnetic resonance imaging (MRI)-guided focal laser ablation (FLA) therapy is an attractive modality for such an approach. In FLA therapy, accurate placement of laser fibers is critical to ensuring that the full target volume is ablated. In practice, error in needle placement is invariably present due to pre- to intra-procedure image registration error, needle deflection, prostate motion, and variability in interventionalist skill. In addition, some of these sources of error are difficult to control, since the available workspace and patient positions are restricted within a clinical MRI bore. In an attempt to take full advantage of the utility of intraprocedure MRI, while minimizing error in needle placement, we developed an MRI-compatible mechatronic system for guiding needles to the prostate for FLA therapy. The system has been used to place interstitial catheters for MRI-guided FLA therapy in eight subjects in an ongoing Phase I/II clinical trial. Data from these cases has provided quantification of the level of uncertainty in needle placement error. To relate needle placement error to clinical outcome, we developed a model for predicting the probability of achieving complete focal target ablation for a family of parameterized treatment plans. Results from this work have enabled the specification of evidence-based selection criteria for the maximum target size that can be confidently ablated using this technique, and quantify the benefit that may be gained with improvements in needle placement accuracy.

Canadian Urological Association journal, May 1, 2013

European Radiology, Apr 25, 2018

Objectives To evaluate the feasibility and safety of focal therapy for low-intermediate risk pros... more Objectives To evaluate the feasibility and safety of focal therapy for low-intermediate risk prostate cancer (PCa) with magnetic resonance-guided high frequency focused ultrasound (MRgFUS) Methods This IRB-approved phase 1 prospective study enrolled eight patients with prostate specific antigen (PSA) ≤ 10 ng/ml, ≤ cT2a and Gleason score ≤ 7 (4 + 3) disease following informed consent. Under MRI guidance, focused high frequency ultrasound energy was delivered to ablate the target tissue. Treatment-related adverse events were recorded. Oncologic outcomes were evaluated with multiparametric MRI, PSA and TRUS biopsy at 6 months following treatment. Results Ten target lesions [six Gleason 6 lesions, two Gleason 7 (3 + 4) and two Gleason 7 (4 + 3)] were treated in eight men (prostate volume range, 25-50 cc; mean MRI time, 248 min per patient; mean sonication duration, 65 min). Mean target volume was 2.7 cc and mean post-treatment non-perfused volume was 4.3 cc. Quality of life parameters were similar between baseline and 6 months in 6/8 patients. All treated regions were negative on MRI; 4/8 patients and 6/10 target lesions (60%) were clear of disease on biopsy. One patient with 2-mm Gleason 8 disease in one of five cores from treatment site (4 + 3 disease at baseline) subsequently underwent prostatectomy with negative surgical margins. Three patients with low volume (5-15%) Gleason 6 residual disease were offered active surveillance. Mean PSA decreased from 5.06 at baseline to 3.4 ng/ml at 6 months. Conclusion MRgFUS is a feasible and safe method of noninvasively ablating low-intermediate risk PCa with acceptable shortterm oncologic outcomes. Key Points • Focal therapy selectively ablates locally confined, clinically significant index lesion with a margin while sparing rest of gland and adjacent vital structures. • Magnetic resonance-guided focused high frequency ultrasound surgery (MRgFUS) combines MRI with HIFU. • MRgFUS provides ability to monitor treatments in real time and allows a targeted approach for focal ablation. • MRgFUS is a feasible, safe method of noninvasively ablating low-intermediate risk PCa. • MRgFUS provides acceptable oncologic outcomes at 6 months.

The Journal of Urology, Apr 1, 2009

Results: The robot is fully operational within a closed bore MRI system. The ultrasonic motors le... more Results: The robot is fully operational within a closed bore MRI system. The ultrasonic motors lend to compact design (width 30 cm) that allows for trans-perineal prostatic procedures within the closed bore of a high resolution MRI device. To date, all testing was ...

Future Oncology, Jun 1, 2011

Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in ... more Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in oncology. For example, partial nephrectomy is now accepted as a preferred alternative over radical nephrectomy for small (up to 4 cm or T1) tumors. Focal therapy (FT) is another organ-preserving strategy applying energy (cryotherapy, laser ablation and/or high-intensity focused ultrasound) to destroy tumors while leaving the majority of the organ, surrounding tissue and structures unscathed and functional. Owing to the perceived multifocality of prostate cancer (PCa) technology limitations, in the past PCa was not considered suitable for FT. However, with the rise of active surveillance for the management of low-risk PCa in carefully selected patients, FT is emerging as an alternative. This is owing to technology improvements in imaging and energy-delivery systems to ablate tissue, as well as the realization that many men and clinicians still desire tumor control. With the postulated ability to ablate tumors with minimal morbidity, FT may have found a role in the management of PCa; the aim of FT a being long-term cancer control without the morbidity associated with radical therapies. Data for FT in PCa have been derived from case series and small Phase I trials, with larger cohort studies with longer followup having only just commenced. More data from large trials on the safety and efficacy of FT are required before this approach can be recommended in men with PCa. Importantly, studies must confirm that no viable cancer cells remain in the region of ablation. FT might eventually prove to be a 'middle ground' between active surveillance and radical treatment, combining minimal morbidity with cancer control and the potential for retreatment. Keywords n active surveillance n cryotherapy n focal therapy n HIFU n laser n MRI n prostate cancer

European Urology Supplements, Feb 1, 2012

Lecture Notes in Computer Science, 2012

We present a device that has been developed for delivering prostate focal thermal therapy under m... more We present a device that has been developed for delivering prostate focal thermal therapy under magnetic resonance imaging (MRI) guidance. Unlike most existing devices, ours is capable of delivering needles to targets in the prostate without removing the patient from the scanner. This feature greatly reduces procedure time and increases accuracy. The device consists of a mechanical linkage encoded with optical incremental encoders, and is manually actuated. A custom magnetic resonance (MR) compatible alignment interface allows the user to manually align the device to its target with high accuracy inbore in very short time. The use of manual actuation over motors greatly reduces the complexity and bulk of the system, making it much more compact and portable. This is important when dealing with such tight space constraints. Needle targeting experiments in gel phantoms have demonstrated the device's ability to deliver needles with an accuracy of 2.1 +/-1.3 mm.

F1000 Medicine Reports, Dec 8, 2010

This concise review attempts to highlight the recent advances in magnetic resonance imaging (MRI)... more This concise review attempts to highlight the recent advances in magnetic resonance imaging (MRI) in relation to all the different aspects of prostate cancer (PCa), and outlines future implications of MRI in the diagnosis, treatment, and surveillance of PCa.