Methods and systems for targeting & assessing urology organ treatment

Abstract

Systems and methods are provided for treating indications associated with a urological organ (e.g., bladder, kidney, prostate, ureter, or urethra, etc.).

Description

[0001] Atorney Docket No. 58496-0002W01

[0002] Methods and Systems for Targeting & Assessing Urology Organ Treatment

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Application No. 63 / 680,800, filed on August 8, 2024, and U.S. Application No. 63 / 794,450, filed on April 25, 2025, the contents of each are hereby incorporated by reference.

[0005] TECHNICAL FIELD

[0006] Systems and methods are provided for treating and assessing a urology organ / tissue (e g., prostate, kidney, bladder, urethra, ureter).

[0007] BACKGROUND

[0008] Benign Prostatic Hyperplasia (BPH) is a non-cancerous enlargement (benign adenoma) of the prostate gland commonly affecting older men. It typically starts developing in men over the age of 40 and becomes more prevalent with advancing age, affecting approximately 50% of men by age 60 and up to 90% by age 85. BPH can lead to uncomfortable urinary symptoms (lower urinary' tract symptoms or LUTS) such as frequent urination, difficulty starting urination, weak urine stream, and the inability to completely empty the bladder. While BPH itself is not life-threatening, it can significantly impact the quality of life and, if left untreated, may result in complications such as urinary tract infections, bladder stones, and, in severe cases, kidney damage.

[0009] Treatment options for BPH range from lifestyle changes and medications to various surgical procedures, depending on the severity of symptoms. Some minimally invasive procedures, like transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA), use heat to reduce prostate size. Surgical options include transurethral resection of the prostate (TURP), which is the most common and involves removing part of the prostate. While these treatments can be effective, they come with limitations, such as the risk of complications from surgery, and the possibility7that symptoms may recur over time, necessitating further treatment. Atorney Docket No. 58496-0002W01

[0010] Prostate cancer is a malignant tumor of the prostate that is projected to impact 1 :8 men and rise in incidence with age. Prostate cancer used to be entirely removed or radiated. However, it has been treated with ablation modalities that also can be used in

[0011] BPH.

[0012] Additionally, the genitourinary tract is an epithelium lined channel that spans from the urethral meatus, urethra, (prostatic urethra in men), the bladder, both right and left ureters, and finally the collecting system of both the right and left kidney. This entire tract has been mainly visualized by white light with endoscopy. Blue light with an intravesical agent has been used in the past but was not well adopted.

[0013] SUMMARY

[0014] Ablation can be used successfully to treat or ameliorate symptoms associated with benign or cancerous enlargement of genitourinary tissues including the prostate, bladder, kidney, ureter, or urethra. There is a need for visually observing ablation processes in real-time to ensure that the tissue is being ablated. Accordingly, provided herein are methods for treating an indication associated with the prostate or indications associated with the genitourinary tract.

[0015] In some embodiments, provided herein are methods for treating a prostate, bladder, kidney, ureter, or urethra of a patient, comprising the steps of: inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; inserting a non-mucosal-disrupting ablation system into the patient, ablating a portion of a prostate, bladder, kidney, ureter, or urethra of the patient using the non-mucosal- disrupting ablation system; and using the perfusion visualization system to detect perfusion or lack of perfusion in real time in the prostate, bladder, kidney, ureter, or urethra to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

[0016] In some embodiments, the perfusion visualization system is delivered trans- urethrally.

[0017] In some embodiments, the visualization system is an endoscope or a cystoscope, preferably a flexible or rigid cystoscope, or a flexible or rigid ureteroscope. Atorney Docket No. 58496-0002W01

[0018] In some embodiments, using the perfusion visualization system comprises detecting a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0019] In some embodiments, using the visualization system comprises detecting a combination of both a dye-based reagent and a dye-free tool. In some instances, the dye-free tool is laser speckle. In some instances, the method further comprises intravenously administering the dye-based reagent to the patient. In some instances, the dye-based reagent is administered immediately before or immediately after the ablating step. In some instances, the dye-based reagent is administered 30 seconds to 30 minutes prior to the ablating step. In some instances, the dye-based reagent is administered 30 seconds to 30 minutes after the ablating step. In some instances, the dye-based reagent appears in the prostate, bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of administering the dye-based reagent to the patient, and the perfusion visualization system is used to detect perfusion or lack of perfusion in real time in the prostate, bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of the administration. In some instances, the dye-based reagent clears from the patient’s prostate, bladder, kidney, ureter, or urethra within 10 minutes to 30 minutes of administering the dye-based reagent to the patient. In some instances, the dyebased reagent is indocyanine green (ICG) angiography, riboflavin, or fluoresceine. In some instances, the dye is ICG. In some instances, the dye is administered to the patient at a concentration range of about 1 mg / ml to about 5 mg / ml. In some instances, the dose of the dye that is administered to the patient is about 0.5 to 10 mg, e.g., 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg. 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg. 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. 10.0 mg (e.g., 5.0 mg).

[0020] In some embodiments, the non-mucosal-disrupting ablation system is delivered trans-urethrally, trans-perineally, trans-abdominally, or trans-rectally.

[0021] In some embodiments, the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor / steam, laser, electroporation, cryoablation, high intensity focal ultrasound, or microwave methods. In some instances, the non- mucosal disrupting ablation system is a water vapor / steam system and is delivered trans-urethrally. Atorney Docket No. 58496-0002W01

[0022] In some embodiments, the patient has benign prostatic hyperplasia or prostate cancer.

[0023] Also provided herein are systems for ablating prostate, bladder, kidney, ureter, or urethra tissue, the system comprising: a visualization system for trans-urethral delivery' into a bladder, kidney, ureter, or urethra collecting system, and a non- mucosal disrupting ablation system.

[0024] In some embodiments, the visualization system is an endoscope, a cystoscope, preferably a flexible or rigid cystoscope, or a flexible or rigid ureteroscope.

[0025] In some embodiments, the visualization system comprises using a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0026] In some embodiments, the non-mucosal-disrupting ablation system utilizes one of the following methods: water vapor / steam, laser, electroporation, cryoablation, high intensity' focal ultrasound, or microwave methods.

[0027] In some embodiments, the non-mucosal-disrupting ablation system is for trans-urethral, trans-permeal, trans-abdominal, or trans-rectal delivery'.

[0028] In some embodiments, provided herein are methods for treating a prostate of a patient, comprising the steps of: inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; inserting anon-mucosal disrupting ablation system into the patient, ablating a portion of a prostate of the patient using the vapor / ablation delivery' system; and using the visualization system to detect perfusion or lack of perfusion in real time in the prostate to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

[0029] In some embodiments, the visualization system is delivered trans-urethrally.

[0030] In some embodiments, the visualization system is an endoscope or a cystoscope (e.g., a flexible or rigid cystoscope).

[0031] In some embodiments, the visualization system comprises a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0032] In some embodiments, the visualization system comprises a combination of both a dye-based reagent and a dye-free tool. In some instances, the dye-free tool is laser speckle. In some instances, the method further comprises intravenously Atorney Docket No. 58496-0002W01 administering the dye-based reagent to the patient. In some instances, the administering of the dye-based reagent is immediately before or immediately after the ablating step. In some instances, the dye-based reagent is administered 30 seconds to 30 minutes prior to the ablating step. In some instances, the dye-based reagent is administered 30 seconds to 30 minutes after the ablating step. In some instances, the dye-based reagent appears in the prostate within 15 seconds to 5 minutes of administering the dye-based reagent to the patient, and the visualization system is used to detect perfusion or lack of perfusion in real time in the prostate within 15 seconds to 5 minutes of the administration. In some instances, the dye-based reagent clears from the patient's prostate within 10 minutes to 30 minutes of administering the dye-based reagent to the patient. In some instances, the dye-based reagent is indocyanine green (ICG) angiography, riboflavin, or fluoresceine. In some instances, the dye is ICG. In some instances, the dye is administered to the patient at a concentration range of about 1 mg / ml to about 5 mg / ml. In some instances, the dose of the dye that is administered to the patient is about 0.5 to 10 mg, e.g., 0.5 mg. 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg (e.g., 5.0 mg).

[0033] In some embodiments, the non-mucosal disrupting ablation system is delivered trans-urethrally, trans-perineally, trans-abdominally, or trans-rectally.

[0034] In some embodiments, the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor steam, laser, electroporation, cryoablation, high intensity focal ultrasound, or microwave methods. In some instances, the non- mucosal disrupting ablation system is a water vapor steam system and is delivered trans-urethrally.

[0035] In some embodiments, the patient has benign prostatic hyperplasia or prostate cancer.

[0036] Also provided herein are systems for ablating prostate tissue, the system comprising: a visualization system for trans-urethral delivery into a bladder, kidney, ureter, or urethra collecting system and a non-mucosal disrupting ablation system. In some embodiments, the visualization system is an endoscope or a cystoscope (e.g., a flexible or rigid cystoscope) or flexible or rigid ureteroscope. Atorney Docket No. 58496-0002W01

[0037] In some embodiments, the visualization system comprises a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0038] In some embodiments, the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor steam, laser, electroporation, cry oablation, high intensity focal ultrasound, or microwave methods.

[0039] In some embodiments, the non-mucosal disrupting ablation system is for trans-urethral, trans-perineal, trans-abdominal, or trans-rectal delivery.

[0040] Also described herein are methods for treating a bladder, kidney, ureter, or urethra of a patient, comprising the steps of: inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; inserting a non-mucosal disrupting or mucosal disrupting ablation or biopsy system into the patient, ablating a portion of the bladder, kidney, ureter, or urethra of the patient using the vapor / ablation delivery' system; and using the visualization system to detect perfusion or lack of perfusion in real time in the bladder, kidney, ureter, or urethra to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

[0041] In some embodiments, the visualization system is delivered trans-urethrally.

[0042] In some embodiments, the visualization system is an endoscope or a cystoscope or a ureteroscope (e.g.. a flexible or rigid cystoscope).

[0043] In some embodiments, the visualization system comprises a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0044] In some embodiments, the visualization system comprises a combination of both a dye-based reagent and a dye-free tool.

[0045] In some embodiments, the dye-free tool is laser speckle.

[0046] In some embodiments, the method further comprises intravenously administering the dye-based reagent to the patient.

[0047] In some embodiments, administering of the dye-based reagent is immediately before or immediately after the ablating step.

[0048] In some embodiments, the dye-based reagent is administered 30 seconds to 30 minutes prior to the ablating step. Atorney Docket No. 58496-0002W01

[0049] In some embodiments, the dye-based reagent is administered 30 seconds to 30 minutes after the ablating step.

[0050] In some embodiments, the dye-based reagent appears in the bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of administering the dye-based reagent to the patient, and the visualization system is used to detect perfusion or lack of perfusion in real time in the bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of the administration.

[0051] In some embodiments, the dye-based reagent clears from the patient’s bladder, kidney, ureter, or urethra within 10 minutes to 30 minutes of administering the dyebased reagent to the patient.

[0052] In some embodiments, the dye-based reagent is indocyanine green (ICG) angiography, riboflavin, or fluoresceine.

[0053] In some embodiments, the dye is ICG.

[0054] In some embodiments, the dye is administered to the patient at a concentration range of about 1 mg / ml to about 5 mg / ml.

[0055] In some embodiments, the dose of the dye that is administered to the patient is about 0.5 to 10 mg, e.g., 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg. 10.0 mg (e.g., 5.0 mg).

[0056] In some embodiments, the non-mucosal disrupting ablation system is delivered trans-urethrally, trans-perineally, trans-abdominally, or trans-rectally.

[0057] In some embodiments, the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor steam, laser, electroporation, cry oablation, high intensity’ focal ultrasound, or microwave methods.

[0058] In some embodiments, the non-mucosal disrupting ablation system is a water vapor steam system and is delivered trans-urethrally.

[0059] Also provided are systems for ablating bladder, kidney, ureter, or urethra tissue, the system comprising: a visualization system for trans -urethral delivery into a bladder, kidney, ureter, or urethra collecting system and a mucosal or a non-mucosal disrupting ablation system.

[0060] In some embodiments, the visualization system is an endoscope or a cystoscope (e.g., a flexible or rigid cystoscope) or flexible or rigid ureteroscope. Atorney Docket No. 58496-0002W01

[0061] In some embodiments, the visualization system comprises a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

[0062] In some embodiments, the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor steam, laser, electroporation, cry oablation, high intensity focal ultrasound, or microwave methods.

[0063] In some embodiments, the non-mucosal disrupting ablation system is for trans-urethral, trans-perineal, trans-abdominal, or trans-rectal delivery.

[0064] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1 , 2, or 3 is equivalent to greater than or equal to 1 , greater than or equal to 2, or greater than or equal to 3.

[0065] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0066] Certain inventive embodiments herein contemplate numerical ranges. When ranges are present, the ranges include the range endpoints. Additionally, every sub range and value within the range is present as if explicitly written out.

[0067] The term “about” means + / - 10% of a given value.

[0068] The term “real time” or “real-time,” as used interchangeably herein, generally refers to an event (e.g., an operation, a process, a method, a technique, a computation, a calculation, an analysis, a visualization, an optimization, etc.) that is performed using recently obtained (e.g., collected or received) data. In some cases, a real time event may be performed almost immediately or within a short enough time span, such as within at least 0.0001 millisecond (ms), 0.0005 ms, 0.001 ms, 0.005 ms, 0.01 ms, 0.05 ms, 0.1 ms, 0.5 ms, 1 ms, 5 ms, 0.01 seconds, 0.05 seconds, 0.1 seconds, 0.5 seconds, 1 second, or more. In some cases, a real time event may be performed almost immediately or within a short enough time span, such as within at most 1 second, 0.5 Atorney Docket No. 58496-0002W01 seconds, 0.1 seconds, 0.05 seconds, 0.01 seconds, 5 ms, 1 ms. 0.5 ms, 0.1 ms, 0.05 ms. 0.01 ms, 0.005 ms, 0.001 ms, 0.0005 ms, 0.0001 ms, or less.

[0069] As used herein, the terms “subject’’ and “patient” are used interchangeably. As used herein, the terms “subject” and “subjects” refers to an animal (e.g., birds, reptiles, and mammals), a mammal including a primate (e.g., a monkey, chimpanzee, and a human) and a non-primate (e.g., a camel, donkey, zebra, cow, pig, horse, cat. dog, rat, and mouse). In certain embodiments, the mammal is 0 to 6 months old, 6 to 12 months old, 1 to 5 years old, 5 to 10 years old, 10 to 15 years old, 15 to 20 years old, 20 to 25 years old, 25 to 30 years old, 30 to 35 years old, 35 to 40 years old, 40 to

[0070] 45 years old, 45 to 50 years old, 50 to 55 years old, 55 to 60 years old, 60 to 65 years old, 65 to 70 years old. 70 to 75 years old. 75 to 80 years old, 80 to 85 years old, 85 to

[0071] 90 years old, 90 to 95 years old or 95 to 100.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0073] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

[0074] DESCRIPTION OF DRAWINGS

[0075] FIG. 1 is an image showing an exemplary equipment set-up. This includes an endoscope (Part 1) that has capabilities to view dye free / laser speckle and dye based / ICG perfusion in tissue. In addition, there is a tower system (Part 3) that has a camera, light source, and imaging system that can detect dye based / ICG signals. Interpositioned between the endoscope lens and the tower is a dual dye free and dye based sensor camera that connects the two components (Part 2) (note- laparoscope is generic for any endoscope or cystoscope).

[0076] FIG. 2 is an image showing endoscopic (cystoscopic) dye free visualization of blood perfusion of the untreated prostatic urethra. A cystoscope was inserted into the Atorney Docket No. 58496-0002W01 urethra and under white light, the prostatic urethral was visualized at the level of the verumontanum. The dye free / laser speckle view was activated and the superficial perfusion was documented qualitatively and quantitatively. This step was the initial “Mapping Baseline” Stage.

[0077] FIG. 3 is an image showing vapor steam treatment of tissue with dye free endoscopic (cystoscopic) visualization of blood perfusion of the treated prostatic urethra. The cystoscope was removed and the water vapor treatment device was employed. Under white light and laser speckle, the device was placed into the prostatic urethra. The needle was deployed and the laser speckle was turned on to detect the superficial treatment before, during, and after treatment. Qualitative and quantitative data with the laser speckle was then recorded.

[0078] FIG. 4 is an image showing endoscopic (cystoscopic) dye (ICG) visualization of prostatic urethra after ablation (left lobe- right side of the screen) and untreated (right lobe- left side of the screen) of the prostate. After ablation treatment, 2 ml of ICG dye at a concentration 2.5 mg / ml was given to the patient and the ICG phase detection was turned on to a setting that is the lowest without autofluorescence. The treated side showed no fluorescence while the untreated side showed a strong perfusion and ICG signal.

[0079] FIG. 5 is an image showing triphasic (white light, dye free perfusion, dye based perfusion) endoscopic (cystoscopic) visualization of the prostatic urethra. When all three phases of perfusion detection were used after treatment, missed ablation sites were detected by all three phases or by one or two of the phases. These areas can then be re-treated in real time.

[0080] FIG. 6 is an image showing post ablation treatment that was assessed by dye based endoscopic (cystoscopic) visualization. This area had persistent perfusion after water vapor treatment as shown by a strong ICG signal. In this situation, the needle was subsequently deployed and the tissue was then effectively treated. The ICG was subsequently trapped in the tissue since the perfusion had been disrupted.

[0081] FIG. 7 is an image showing post ablation treatment that was assessed by Dye Free endoscopic (cystoscopic) visualization. In this situation, after re-treatment of an ICG positive area, the ICG dye persists, as such, dye free / laser speckle can be used to assess superficial perfusion which will not be affected by residual ICG dye. Atorney Docket No. 58496-0002W01

[0082] FIG. 8 is an image showing rigid cystoscopy to visualize real time perfusion of the bladder and prostate transurethrally. The rigid cystoscope can have a lens that is compatible with a dye-based perfusion system such as ICG or the lens can be connected to a camera sensor that can detect ICG signal along with the monitor output.

[0083] FIG. 9 is an image showing the possibility of using a flexible cystoscopy along with a transperineal approach to tissue ablation. The flexible cystoscope is more comfortable for the patient and can be done in an office setting rather than the operating room under general anesthesia. Multiple ablative technologies can be used transperineally to reach and ablate prostate tissue.

[0084] FIG. 10 is an image showing a flexible perfusion detection system transurethrally with a transperineal cryoablation needle system which can be used to ablate BPH or prostate cancer tissue. The patient is placed in dorsal lithotomy with the trans urethral perfusion visualization via a cystoscope. The transrectal ultrasound detects the transurethral cystoscope but can also visualize the transperineal needles which are placed to allow for ablation of tissue. In this case, the image shows cryoablation needles that utilized argon gas to freeze. However, they could be laser fibers, electroporation needles, microwave needles, or a transrectal HIFU (high intensity focused ultrasound) treatment probe.

[0085] FIG. 11 is an image illustrating that although there is one way to monitor tissue ablation and perfusion disruption transurethrally, there are many approaches (transperineal, transabdominal, transrectal) for the ablative technology7to reach the prostate.

[0086] FIG. 12 is an image illustrating that the triphasic visualization of perfusion not only pertains to prostate but also to bladder, the ureters, and the renal collecting system since they can have perfusion monitors in a transluminal way.

[0087] FIG. 13 is an image of the human urinary' tract, showing where endoscopy can be done. Specifically, the urethra, bladder, ureters, and collecting system of the kidneys are all locations for endoscopy.

[0088] FIG. 14 is an image showing ablation of the prostate and use of the ICG-tissue ablation technique (using water vapor ablation of the prostate tissue). This showed the state of perfusion in the prostate after treatment on the left side of the prostate (right side of the screen). No perfusion was observed there but perfusion was observed on Atorney Docket No. 58496-0002W01 the contralateral side and the middle where no treatment had been administered yet. This showed adequate treatment of the left prostate lateral lobe and the need for treatment of the right lateral lobe. White light (smaller picture) showed minimal differences between the two sides highlighting the advantage of using ICG visualization.

[0089] FIG. 15 are images showing assessment of urethral viability after percutaneous prostate ablation. Flexible cystoscopy after ICG IV infusion, but before cryoablation showed good perfusion (left side of the figure) with ICG and white light visualization. Then the urethral warmer was placed and the cr oablation was started. After the ablation, the urethral warmer was removed, and repeat ICG IV infusion with white light and fluorescence visualization by flexible cystoscopy showed maintained perfusion and urethral viability (right side of the figure).

[0090] FIG. 16 are images show ing the bladder and a bladder tumor with white light and Laser Speckle (LSI) superficial perfusion. Top left comer- bladder wall with white light and LSI. Top right comer show s a papillary tumor of the bladder on white light and increased surrounding superficial perfusion around the tumor. Bottom right show s a papillary tumor on white light with increased superficial perfusion of a feeding blood vessel to the tumor. Bottom left shows a papillary tumor on white light with superficial perfusion of the blood vessel and tumor. Laser speckle shows increased perfusion with white color and decreased perfusion with gray / black color.

[0091] FIG. 17 are images showing a bladder tumor with white light and ICG before and after treatment. Left side of figure show s bladder tumor with white light and also after ICG infusion. Top right side of the figure show s bladder tumor being removed under white light and ICG visualization. Bottom right side of the figure shows white light and ICG visualization after the tumor has been removed.

[0092] FIG. 18 are images showing the urethra with white light and laser speckle that portrays superficial perfusion (left side) and with white light and ICG visualization of Normal Urethra (right side). Laser speckle showed increased perfusion with lighter / brighter color and decreased perfusion with darker color (the color spectrum is shown on the right within each panel of the image).

[0093] FIG. 19 are images showing the urethra with white light and ICG visualization of normal urethra showing good perfusion (left side) and the right side of the figure Atorney Docket No. 58496-0002W01 shows white light and ICG visualization of stricture that demonstrated much less perfusion in comparison.

[0094] FIG. 20 are images showing visualization with white light and laser speckle (right side) and with white light and ICG visualization (left side) of the bladder neck. Both show good perfusion at the bladder neck but if there was a contracture, there would be much less perfusion. Laser speckle shows increased perfusion with lighter / brighter color and decreased perfusion with darker color (the spectrum is shown within the image).

[0095] FIG. 21 are images showing white light and laser speckle (LSI) visualization of the ureter. Left side shows normal ureter with a flexible ureteroscope (no wire). Right top shows normal proximal ureter with semi rigid ureteroscope (wire in place). Right bottom shows mid normal ureter with semi rigid ureteroscope (wire in place). Laser speckle shows increased perfusion with lighter color and decreased perfusion with darker color (the spectrum is shown within the image).

[0096] FIG. 22 are images showing white light and ICG visualization of normal ureter with rigid scope of perfusion. The wire was in place and the intense fluorescence signified good perfusion in the distal, mid, and proximal ureter.

[0097] FIG. 23 are images showing white light and ICG visualization of a normal ureter. Rigid scope of perfusion shows less fluorescence as the ureteral stricture is approached.

[0098] FIG. 24 are images of showing white light and ICG visualization of a ureteral stricture, with rigid scope of perfusion (much less blood flow within stricture than normal, based on the less fluorescence observed).

[0099] FfG. 25 are images of showing white light and ICG visualization of ureteral mass with a flexible scope of perfusion (more blood flow within ureteral mass than normal).

[0100] FIG. 26 are images of showing white light and ICG visualization of ureteral mass with a flexible scope of perfusion (more blood flow within ureteral mass than normal).

[0101] FIG. 27 are images of showing white light and ICG visualization of a kidney with a flexible scope of perfusion in the collecting system. Laser speckle shows increased perfusion with lighter color and decrease perfusion with darker color (the spectrum in beside the image). Atorney Docket No. 58496-0002W01

[0102] FIG. 28 are images of showing white light and ICG visualization of a kidney with a flexible scope (pyeloscopy) of perfusion in the collecting system. The collecting system showed good perfusion.

[0103] FIG. 29 are images of showing white light and ICG visualization of a kidney with a flexible scope (pyeloscopy; retroflexion) of perfusion in the collecting system. Fluorescence is minimal due to the retroflexion and increased distance from the mucosa.

[0104] FIG. 30 shows a dot plot and bar graphs of a REZUM patient’s IPSS (International Prostate Symptom Score) scores and change in scores. Voided volumes and change in voided volumes. The IPSS scores decreased while the voided volumes increased with effective treatment.

[0105] FIG. 31 shows bar graphs of REZUM patient’s flow velocity (maximal and average). Both increased after treatment.

[0106] FIG. 32 shows bar graphs of active REZUM (3 months) patient’s IPSS scores and change in scores. Voided volumes and change in voided volumes. The IPSS scores decreased while the voided volumes increased after treatment.

[0107] FIG. 33 shows bar graphs of active REZUM (3 months) patient’s post void residual (PVR) and flow7time absolute numbers and change.

[0108] FIG. 34 show bar graphs of active REZUM (3 months) patient’s flow velocity (maximal and average). Both increased after treatment.

[0109] FIG. 35 is a table comparing REZUM alone with REZUM that has been done with laser speckle and ICG visualization (Active REZUM) from 3 months and 6 months post operative. The degree of change with REZUM. Active REZUM (3 months), and Active REZUM (6 months) have been compared and ”p values” calculated. As shown the Active REZUM at both 3- and 6- months post op were markedly better than REZUM alone. The real time visualization of blood flow to tissue allow ed targeted ablation to areas that w ere not adequately treated. Without the perfusion visualization, there can be additional viable prostate tissue which would make the alleviating of urinary symptoms and urinary flow less significant.

[0110] FIG. 36 show- bar graphs of active REZUM (6 months) patient’s IPSS scores and change in scores. Voided volumes and change in voided volumes. The IPSS scores decreased while the voided volumes increased after treatment. Atorney Docket No. 58496-0002W01

[0111] FIG. 37 show bar graphs of active REZUM (6 months) patient’s flow velocity' (maximal and average). Both increased after treatment.

[0112] FIG. 38 are diagrams for a urodynamics study that was done before vapor steam treatment with triphasic visualization (white light, laser speckle, and ICG). The diagrams show that the bladder detrusor pressure needed to void is very high due to obstructing prostate tissue. The pressure flow nomogram shows that the voiding pattern is in the obstructed region.

[0113] FIG. 39 are diagrams for a urodynamics study 1-year after vapor steam treatment with triphasic visualization (white light, laser speckle, and ICG) shows that the bladder detrusor pressure is lowered and the pressure flow' nomogram is out of the obstructed region but mainly in the non-obstructed region.

[0114] DETAILED DESCRIPTION

[0115] Traditionally, transurethral surgery of the prostate involved breach of the mucosa w ith destruction of prostate tissue. As a result, there w as no need to monitor the tissue in real time. However, recently techniques and technology’ have used either transurethral or transperineal approaches to ablate prostate tissue without breach of the mucosa. After ablation, there is no clear way to monitor the tissue effects in real time. Accordingly, provided herein are methods for monitoring the tissue effects in real time to guide the surgeon to target tissue ablation. The present application relates generally to methods and systems using medical imaging to quantify and assess perfusion (or lack thereof) in or near a prostate of a subject. The systems and methods of the present disclosure may be implemented to measure perfusion and blood flow' (or lack thereof).

[0116] In the genitourinary’ tract, the most distal point is the urethral meatus which extends proximally as the urethra. Disease of this area can include (but not limited to) cancer, benign tumors, strictures, stones, and infections. Treatment options can include (but not limited to) ablation, excision, balloon treatment, fragmentation, extraction and chemical application / inj ection. The bladder is more proximal, and diseases of this area can include (but not limited to) cancer, benign tumors, strictures, stones, and infections. Treatment options can include (but not limited to) ablation, excision, and chemical application / inj ection. Additionally, the ureters (right and left) are also more proximal and disease of this area can include (but not limited to) cancer, benign tumors, strictures, stones, and infections. Treatment options can include (but Atorney Docket No. 58496-0002W01 not limited to) ablation, excision, balloon treatment, fragmentation, extraction and chemical application / inj ection. Finally, the renal (right and left) collecting system are most proximal. Disease of this area can include (but not limited to) cancer, benign tumors, strictures, stones, and infections. Treatment options can include (but not limited to) ablation, excision, balloon treatment, fragmentation, extraction and chemical application / inj ection.

[0117] The specialized endoscopy with the described methodology in the urethra (urethroscopy), bladder (cystoscopy), ureter (ureteroscopy), and kidney (pyeloscopy) (see, e.g., FIG. 13) allows for the visualization of the surface vasculature that can aid in diagnosis since the detection of blood vessel patterns, enhancement kinetics, and decay is different than when comparing normal to disease states. In addition, after treatment and upon healing, these parameters also can be used to follow resolution of disease.

[0118] Described herein are methods that utilize white light, laser speckle, intravenous ICG. visualization with both rigid and flexible endoscopes with an augmented laser system for diagnosing and treating a variety of indications.

[0119] Methods of Treating a Prostate and / or an Indication associated with genitourinary tract

[0120] The terms “treat” or “treating” refer to accomplishing one or more of the following: (a) reducing the severity of a disease, disorder, condition, or symptom; (b) limiting the development of symptoms characteristic of the disease, disorder, or condition being treated; (c) limiting worsening of symptoms characteristic of the disease, disorder, or condition being treated; (d) limiting recurrence of the disease, disorder, or condition in subjects that have previously had the disease, disorder, or condition; and (e) limiting recurrence of symptoms in subj ects that were previously symptomatic for the disease, disorder, or condition. In some embodiments, “treat” or “treating” herein refers to continuation of the described herein methods until perfusion is no longer visually observed in or near a prostate of a subject.

[0121] Prostate

[0122] Described herein are methods for treating a prostate of a patient, wherein the methods include the steps of inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; inserting a non-mucosal-disrupting Atorney Docket No. 58496-0002W01 vapor / ablation delivery system into the patient, ablating a portion of a prostate (or organ visualized) of the patient using the vapor / ablation delivery system; administering a dye, and using the visualization system to detect perfusion or lack of perfusion in real time in the prostate to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

[0123] In some embodiments, a patient has a disorder of the prostate where the treatment typically requires ablation of a portion of the prostate (e.g., Benign Prostate Hyperplasia or Prostate Cancer). Current treatments for BPH and prostate cancer have converged and become similar. Therefore, the potential to monitor perfusion and tissue ablation in both BPH and prostate cancer would be beneficial. The methods described herein also allow for the monitoring of the mucosa and the submucosal of the bladder as well as upper tract ureteral collecting system of the kidney for tumor detection and ablation.

[0124] The key determination of procedure completion is the closure of vascular flow to the hyperplastic portion of the prostate contributing to LUTS. However, treatment completion has been dependent upon surgical visual assessment of tissue blanching under white light, which is based upon sometimes subtle tissue color changes and is thus technically challenging and maybe inaccurate.

[0125] As such, described herein, the systems and methods allow for real-time visualization of the prostate tissue. The goal of ablation of the prostate for the purposes of treating a prostate disorder is to stop perfusion in that area. As such, the methods herein allow for quantification and assessment of perfusion (or lack thereof) in or near a prostate of a subject.

[0126] Any of the present methods can include a step of identifying a patient in need of treatment. For example, a subject can be examined and / or subjected to clinical tests in order to determine whether they have, for example, a disorder of the prostate where the treatment typically requires ablation of a portion of the prostate (e.g., Benign Prostate Hyperplasia or Prostate Cancer).

[0127] Indications associated with genitourinary tract

[0128] Also described herein are methods for treating an indication associated with genitourinary tract of a patient, wherein the methods include the steps of: inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; Atorney Docket No. 58496-0002W01 inserting a non-mucosal disrupting or mucosal disrupting ablation or biopsy system into the patient, ablating a portion of the bladder, kidney, ureter, or urethra of the patient using the vapor / ablation delivery system; and using the visualization system to detect perfusion or lack of perfusion in real time in the bladder, kidney, ureter, or urethra to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

[0129] In some embodiments, a patient has a disorder of an organ or tissue associated with the genitourinary tract where the treatment typically requires non-mucosal disrupting or mucosal disrupting ablation of a portion of the organ or tissue associated with the genitourinary tract. Current treatments for indications associated with the genitourinary tract have converged and become similar. There are ablation technologies such as cryoablation, laser ablation, steam ablation, and high intensity' ultrasound ablation. They abolish perfusion and cause tissue death. These supplement the older "excision" treatments that disrupt the mucosa such as biopsy and resection devices that have electrical current or are ‘‘cold” without. The electrical current can be used to ablate the blood vessels as well. Therefore, the potential to monitor perfusion and tissue ablation for indications associated with the genitourinary' tract would be beneficial. The methods described herein also allow for the monitoring of the mucosa and the submucosal of the genitourinary tract for tumor detection and ablation and efficacy assessment.

[0130] The key determination of procedure completion is the loss of perfusion: stoppage of vascular flow' to the hyperplastic portion of the compromised tissue / organ of the genitourinary tract. However, determination of treatment completion has been dependent upon surgical visual assessment of tissue under white light, which is based upon subtle tissue color changes and tissue defect, and is technically challenging and can be inaccurate.

[0131] As such, the systems and methods described herein allow for real-time visualization of the organ or tissue associated with the genitourinary tract. The goal of ablation of the organ or tissue associated with the genitourinary tract for the purposes of treating an indication that is associated w ith the genitourinary' tract is to stop perfusion in that area. The methods described herein allow for quantification and Atorney Docket No. 58496-0002W01 assessment of perfusion (or lack thereof) in or near the organ or tissue associated with the genitourinary tract of a subject.

[0132] Any of the present methods can include a step of identifying a patient in need of treatment. For example, a subject can be examined and / or subjected to clinical tests in order to determine whether they have, for example, a disorder of the bladder, kidney, ureter, or urethra where the treatment typically requires ablation of a portion of the bladder, kidney, ureter, or urethra.

[0133] Non-mucosal Disrupting Ablation Systems

[0134] Ablation is a means for removing tissue. In the context of the prostate, ablative technologies are well known and include a variety of different technologies. Ablation therapies contemplated by the methods described herein include any technologies that do not breach the mucosa and that may be delivered trans -urethrally (such as the water vapor steam therapy), trans-perineally, trans-abdominally, or trans-rectally. Exemplary ablation technologies include cryoablation, electroporation, microwave ablation, laser ablation, water vapor or steam ablation, and high intensity ultrasound ablation.

[0135] Water vapor (steam) therapy is a minimally invasive treatment for BPH that uses steam to reduce prostate tissue. The benefits of w ater vapor therapy include a significant reduction in urinary symptoms, improved quality of life, and preservation of sexual function, with a low risk of side effects. The procedure is relatively quick, ty pically performed outpatient, and involves minimal recovery time compared to traditional surgeries. Additionally, Water vapor therapy can be an effective option for patients who do not respond well to medications or prefer to avoid the potential risks and complications of more invasive surgical procedures.

[0136] The water vapor system administers precise, controlled doses of stored thermal energy in water vapor directly to the obstructive tissue in the prostate gland responsible for lower urinary tract symptoms (LUTS) secondary’ to BPH. Each 9- second treatment uses 0.42 ml of heated sterile water vapor, which quickly and evenly disperses through the tissue interstices. As the w ater vapor condenses, it releases the stored thermal energy’, denaturing cell membranes and causing immediate cell death along w ith the closure of blood vessels. Water vapor steam therapies contemplated Atorney Docket No. 58496-0002W01 herein are ones, such as the one described in U.S. Patent Application No. 2024 / 0081885.

[0137] Success of an ablation procedure can be determined using perfusion tools in a method as described herein. Perfusion assessment not only allows target areas for ablation to be visualized, but is also helpful in determining if the procedure was successful or not.

[0138] Mucosal Disrupting Ablation Systems

[0139] Mucosal disrupting ablation systems are endoscopic techniques used to remove or destroy damaged / tumor tissue, and are well known in the art. Common types include sharp tissue removal and electrical resectoscope devices. It also can include laser ablation, radiofrequency ablation, cryoablation, and ultrasound ablation when they disrupt the mucosa. Like non-mucosal disrupting ablation systems, these may be delivered trans-urethrally, trans-perineally, trans-abdominally, or trans-rectally and can be monitored using perfusion tools as outlined below.

[0140] Perfusion Visualization Systems and Tools

[0141] Dye-based reagents

[0142] In some embodiments of the methods described herein, a subject is given a dye-based reagent prior to. during, or after completion of the ablation procedure. Examples of dye-based reagents include indocyanine green (ICG) angiography, riboflavin, fluoresceine, etc. ICG is a water-soluble cyanine dye which shows fluorescence in the near infrared range, with peak spectral absorption of about 790 nm in blood. In some cases, ICG is introduced into the blood stream (i.e.. intravenously). The dye can then flow into areas that experience blood flow. Upon excitation in the area of interest, the ICG will fluoresce where it is present. The near IR fluorescence can be measured on a near-IR sensitive detector. Riboflavin, also known as Vitamin B2. can also be used for fluorescence imaging. Riboflavin fluoresces yellow-green when exposed to light. Fluorescein fluoresces yellow-green when exposed to light and has an absorption maximum at 494 nm and emission maximum of 512 nm (in water).

[0143] In some embodiments, a fluorescent dye-based reagent (e.g., ICG) can be visualized within the prostate tissue to target areas for ablation and / or confirm the lack of perfusion after treatment. As such, in some instances, a fluorescent dye-based Atorney Docket No. 58496-0002W01 reagent (e.g., ICG) can be given to a subject intravenously immediately (e.g., about 30 minutes or less; about 29 minutes or less; about 28 minutes or less; about 27 minutes or less; about 26 minutes or less; about 25 minutes or less; about 24 minutes or less; about 23 minutes or less; about 22 minutes or less; about 21 minutes or less; about 20 minutes or less; about 19 minutes or less; about 18 minutes or less; about 17 minutes or less; about 16 minutes or less; about 15 minutes or less; about 14 minutes or less; about 13 minutes or less; about 12 minutes or less; about 11 minutes or less; about 10 minutes or less, about 9 minutes or less; about 8 minutes or less; about 7 minutes or less; about 6 minutes or less; about 5 minutes or less; about 4 minutes or less; about 3 minutes or less; about 2 minutes or less; about 1 minute or less; about 50 seconds or less; about 40 seconds or less; about 30 seconds or less; about 20 seconds or less; about 10 seconds or less; about 1 second to about 10 seconds; about 10 seconds to about 20 seconds; about 20 seconds to 30 seconds; about 30 seconds to 1 minute; about 1 minute to about 2 minutes; about 2 minutes to about 3 minutes; about 3 minutes to about 4 minutes; about 4 minutes to about 5 minutes; about 5 minutes to about 6 minutes; about 6 minutes to about 7 minutes; about 7 minutes to about 8 minutes; about 8 minutes to about 9 minutes; about 9 minutes to about 10 minutes; about 10 minutes to about 11 minutes; about 11 minutes to about 12 minutes; about 12 minutes to about 13 minutes; about 13 minutes to about 14 minutes; about 14 minutes to about 15 minutes; about 15 minutes to about 16 minutes; about 16 minutes to about 17 minutes; about 17 minutes to about 18 minutes; about 18 minutes to about 19 minutes; about 19 minutes to about 20 minutes; about 21 minutes to about 22 minutes; about 23 minutes to about 24 minutes; about 24 minutes to about 25 minutes; about 26 minutes to about 27 minutes; about 27 minutes to about 28 minutes; about 28 minutes to about 29 minutes; about 29 minutes to about 30 minutes; preferably, 30 seconds prior to visualizing the ICG effect or 15 minutes for full clearance of ICG prior to ablation or after ablation) prior to the ablation procedure. In some embodiments, a fluorescent dye-based reagent (e.g., ICG) can be given to a subject intravenously immediately (e.g., about 30 minutes or less; about 29 minutes or less; about 28 minutes or less; about 27 minutes or less; about 26 minutes or less; about 25 minutes or less; about 24 minutes or less; about 23 minutes or less; about 22 minutes or less; about 21 minutes or less; about 20 minutes or less; about 19 minutes or less; about 18 minutes or less; about 17 minutes or less; about 16 minutes Atorney Docket No. 58496-0002W01 or less; about 15 minutes or less: about 14 minutes or less; about 13 minutes or less; about 12 minutes or less; about 11 minutes or less; about 10 minutes or less, about 9 minutes or less; about 8 minutes or less; about 7 minutes or less; about 6 minutes or less; about 5 minutes or less; about 4 minutes or less; about 3 minutes or less; about 2 minutes or less; about 1 minute or less; about 50 seconds or less; about 40 seconds or less; about 30 seconds or less; about 20 seconds or less; about 10 seconds or less; about 1 second to about 1 minutes; about 1 second to about 2 minutes; about 1 second to about 3 minutes; about 1 second to about 4 minutes; about 1 second to about 5 minutes; about 1 second to about 30 seconds; about 1 second to about 45 seconds; about 1 minute to about 5 minutes; about 1 minute to about 10 minutes; about 1 minute to about 15 minutes; about 1 minute to about 20 minutes; about 1 minute to about 30 minutes; about 1 second to about 10 seconds; about 10 seconds to about 20 seconds; about 20 seconds to 30 seconds; about 30 seconds to 1 minute; about 1 minute to about 2 minutes; about 2 minutes to about 3 minutes; about 3 minutes to about 4 minutes; about 4 minutes to about 5 minutes; about 5 minutes to about 6 minutes; about 6 minutes to about 7 minutes; about 7 minutes to about 8 minutes; about 8 minutes to about 9 minutes; about 9 minutes to about 10 minutes; about 10 minutes to about 11 minutes; about 11 minutes to about 12 minutes; about 12 minutes to about 13 minutes; about 13 minutes to about 14 minutes; about 14 minutes to about 15 minutes; about 15 minutes to about 16 minutes; about 16 minutes to about 17 minutes; about 17 minutes to about 18 minutes; about 18 minutes to about 19 minutes; about 19 minutes to about 20 minutes; about 21 minutes to about 22 minutes; about 23 minutes to about 24 minutes; about 24 minutes to about 25 minutes; about 26 minutes to about 27 minutes; about 27 minutes to about 28 minutes; about 28 minutes to about 29 minutes; about 29 minutes to about 30 minutes after the ablation procedure.

[0144] In some embodiments the fluorescent dye-based reagent (e.g., ICG) appears in the prostate within 1 minute of administering the reagent to a patient (e.g., within about 5 minutes, within about 4 minutes, within about 3 minutes, within about 2 minutes, within about 1 minute, within about 30 seconds, within about 15 seconds; within about 1 second to about 10 seconds; within about 1 second to about 15 seconds; within about 1 second to about 30 seconds; within about 1 second to about 45 seconds; within about 1 second to about 1 minute). Particularly, the ICG appears in Atorney Docket No. 58496-0002W01 the prostate between about 30 seconds to about 1 minute after giving it to the subject intravenously.

[0145] In some embodiments the fluorescent dye-based reagent (e.g., ICG) clears from the prostate of a subject by about 30 minutes of administering the reagent to a patient (e.g., by about 30 minutes, by about 29 minutes, by about 28 minutes, by about 27 minutes, by about 26 minutes, by about 25 minutes, by about 24 minutes, by about 23 minutes, by about 22 minutes, by about 21 minutes, by about 20 minutes, by about 19 minutes, by about 18 minutes, by about 17 minutes, by about 16 minutes, by about 15 minutes, by about 14 minutes, by about 13 minutes, by about 12 minutes, by about 11 minutes, by about 10 minutes, by about 9 minutes, by about 8 minutes, by about 7 minutes, by about 6 minutes, by about 5 minutes; within about 1 minute to about 30 minutes; within about 5 minutes to about 30 minutes; within about 10 minutes to about 30 minutes; within about 15 minutes to about 30 minutes; within about 1 minute to about 2 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 4 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 6 minutes, about 6 minutes to about 7 minutes, about 7 minutes to about 8 minutes, about 8 minutes to about 9 minutes, about 9 minutes to about 10 minutes, about 10 minutes to about 11 minutes, about 11 minutes to about 12 minutes, about 12 minutes to about 13 minutes, about 13 minutes to about 14 minutes, about 14 minutes to about 15 minutes, about 15 minutes to about 16 minutes, about 16 minutes to about 17 minutes, about 17 minutes to about 18 minutes, about 18 minutes to about 19 minutes, about 19 minutes to about 20 minutes, about 21 minutes to about 22 minutes, about 23 minutes to about 24 minutes, about 24 minutes to about 25 minutes, about 26 minutes to about 27 minutes, about 27 minutes to about 28 minutes, about 28 minutes to about 29 minutes, about 29 minutes to about 30 minutes, preferably, the ICG is cleared or flushed from a subject’s system between about 10 minutes to about 30 minutes).

[0146] In some embodiments, a subject is administered a concentration range of 1 mg / ml to 5 mg / ml of the fluorescent dye-based reagent (e.g., ICG) (which can be administered at different titrations of 1 : 10, 1:50, 1 : 100, 1 : 1000, about 1:5 to about 1 : 10, about 1:5 to about 1:20, about 1 :5 to about 1:30, about 1 :5 to about 1:40, about 1 :5 to about 1 :50, about 1:5 to about 1:60, about 1:5 to about 1 :70, about 1:5 to about 1 :80, about 1:5 to about 1 :90, about 1 :5 to about 1 : 100, about 1:5 to about 1 :250. Atorney Docket No. 58496-0002W01 about 1:5 to about 1 :500. about 1:5 to about 1 :750, about 1 :5 to about 1: 1000, etc.). In some embodiments, the subject is administered a concentration of 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, about 1.0 mg / ml to about 5.0 mg / ml, about 1.0 mg / ml to about 4.5 mg / ml, about 1.0 mg / ml to about 4.0 mg / ml, about 1.5 mg / ml to about 3.5 mg / ml, about 1.5 mg / ml to about 3.0 mg / ml, about 1.5 mg / ml to about 2.5 mg / ml, about 1.5 mg / ml to about 2.0 mg / ml of the fluorescent dye-based reagent (e.g., ICG). In some instances, the concentration is 2.5mg / ml and 1ml is administered to a subject.

[0147] In some embodiments, a subject is administered a total dose of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg. 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg. 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg. 9.0 mg, 9.5 mg, 10.0 mg, about 0.5mg to about 1.0 mg, about 0.5mg to about 1.5 mg, about 0.5mg to about 2.0 mg, about 0.5mg to about 2.5 mg, about 0.5mg to about 3.0 mg, about 0.5mg to about 3.5 mg, about 0.5mg to about 4.0 mg, about 0.5mg to about 4.5 mg, about 0.5mg to about 5.0 mg, about 0.5mg to about 5.5 mg, about 0.5mg to about 6.0 mg, about 0.5mg to about 6.5 mg, about 0.5mg to about 7.0 mg, about 0.5mg to about 7.5 mg, about 0.5mg to about 8.0 mg, about 0.5mg to about 8.5 mg, about 0.5mg to about 9.0 mg, about 0.5mg to about 9.5 mg, about 0.5mg to about 10.0 mg of the fluorescent dye-based reagent (e.g., ICG).

[0148] There are many different systems that can be used to visualize the ICG fluorescence. In some instances, there can be a 4 mM 30-degree lens that is treated to allow visualization of ICG within its wavelength (z.e., specialized lens coatings, particularly anti-reflective and precise bandpass filters optimized for the ICG's excitation and emission wavelengths) that can be used in the different rigid cystoscopy systems. In some instances, there can be a serial connection of two ICG detection units to increase the laser excitation capabilities. In some instances, a unit that has a dual laser can be used which can use non coated lenses for rigid endoscopy or also flexible endoscopy.

[0149] Dye-free tools

[0150] Laser-speckle-contrast imaging (LSCI) represents a non-invasive, nonionizing, and label-free imaging method using coherent monochromatic light where blood flow and tissue perfusion can be detected based on calculated average velocities Atorney Docket No. 58496-0002W01 and red blood cell concentrations. LSCI does not require any dye, is non-contact to the tissue of interest, and can distinguish arteries from veins. LSCI is an imaging method that can give 2-D perfusion maps of large surfaces, and is gaining clinical applications in ophthalmology, rheumatology, neurology, dermatology, and oral surgery. LSCI is based on the principle that the backscattered light from a tissue that is illuminated with coherent laser light forms a random interference pattern at the detector, the so-called speckle pattern.

[0151] In some embodiments, the LSCI system utilized is as described in W02023049401, the entirety of which is incorporated herein by reference.

[0152] In some embodiments, the LSCI system is an accessory to existing surgical laparoscopic and cystoscopic camera systems. As shown in the FIG. 1, the LSCI system is comprised of two components: (1) a reusable imaging module with sensing electronics; (2) a reusable light engine; and (3) bifurcated connecting cable from imaging module and light engine.

[0153] As shown in FIG. 1, the imaging module attaches in-line between a surgical camera and a laparoscopic / endoscopic / cystoscopic coupler, as shown in the diagram. There are stand-alone systems that have an endoscopic lens and camera system capable of detecting ICG signals. The purpose of the imaging module is to retain surgical laparoscopic functionality while diverting key wavelengths of light to the connected sensing electronics for processing. The imaging module is compatible with the standard laparoscopic coupler and the standard laparoscopic camera c-mount. The light engine: 1) controls and emits coherent near-infrared light from the LSCI system's light source (within the Control Unit, which is shown in FIG. 1 as a highlighted unit (Part 2 sensor box) in the Tower (Part 3) that is connected to Part 2 camera); and 2) processes video streams from the sensing electronics and the third- party surgical camera system to produce the system’s augmented display.

[0154] Imaging Module

[0155] The imaging module is a component that attaches between a standard autoclavable surgical laparoscope or cystoscope (e g., a flexible or rigid cystoscope), via a coupler, and a third-party surgical camera. In some embodiments, the autoclavable surgical laparoscope or cystoscope is delivered / inserted into a subject trans-urethral. The imaging module mates to the third-party coupler and to the third- Atorney Docket No. 58496-0002W01 party camera via standard C-mount connection. The imaging module provides a mechanical interface for the sensing electronics at a 90-degree offset from the imaging path. The imaging module is reusable and sterilizable for all surgical procedures. Besides the mounting interfaces, imaging module is comprised of optical elements within a plastic or stainless-steel enclosure.

[0156] Functionally, the imaging module is responsible for diverting longer wavelengths of light (NIR waveband) in the imaging path of the laparoscope to the sensing electronics while passing shorter wavelengths of light (Visible waveband) to the standard third-party7surgical camera. The shorter wavelengths of light are in the visible spectrum and are passed to the third-party' surgical camera to preserve its ability to produce an accurate color image of the patient’s anatomy. There shall be no change to the performance of the third-party laparoscopic camera system. The longer wavelengths of light are in the near-infrared (NIR) spectrum and are diverted to the sensing electronics in order to observe blood flow and tissue perfusion with additional software processing computed within the light engine.

[0157] Sensing Electronics

[0158] The sensing electronics module is contained within the imaging module. The sensing electronics module is comprised of 1) electronics including an imaging sensor, 2) a plastic enclosure, 3) a cable to connect the sensing electronics to the light engine.

[0159] The electronics within the sensing electronics module can have one or more of the following features:

[0160] 1. 60 frames-per-second (FPS) video stream;

[0161] 2. monochrome sensing at a 1920x1080 (1080P HD) pixel resolution;

[0162] 3. CMOS imaging sensor with higher quantum efficiency at NIR wavelengths (between 750nm-1000nm) compared to typical CMOS camera sensors, allowing for more efficient imaging at NIR wavelengths without requiring an excessively high- power light source;

[0163] 4. a one-time-programmable (OTP) memory7device for software expiration. The software will write to the memory' chip when the device is expired and will prevent re-use on another patient; and Atorney Docket No. 58496-0002W01

[0164] 5. a buton, easily accessible by the user, to toggle between the imaging modes (e.g., standby, perfusion view, perfusion overlay).

[0165] Light Engine

[0166] The light engine (LE) should have two or more of the following high-level functions: illumination, data capture, data processing, and image display.

[0167] Illumination: The LE generates narrow bandwidth coherent NIR light that has a discretely programmable wavelength between 750nm and lOOOnm. The LE provides an input on the front of the box to attach a third-party surgical laparoscope light source that feeds the LE with broadband white light. The white light and NIR light are mixed within the LE and then relayed to the surgical site by means of a single light guide cable that is atached to the laparoscope. Although both the white light and NIR light are mixed together and simultaneously illuminate the surgical field, the imaging module ultimately filters the reflected image so that the third-party7camera observes only the reflected response of the white light and the sensing electronics observe only the reflected response of the coherent NIR light.

[0168] Data Capture: The LE captures two streams of video data: 1) a video stream from the CMOS sensor within the sensing electronics module; and 2) a video input that originates from the third-party surgical camera control unit. The third-party video stream is captured by connecting the video output of the third-party camera control unit to the LE.

[0169] Data Processing: The LE contains a computer processor that receives the video stream from the CMOS sensor within the sensing electronics and applies software processing on the incoming data. To visualize blood flow and tissue perfusion, the system uses algorithms related to laser speckle contrast imaging (LSCI) that can provide information about particle velocity in an area. The NIR coherent light source described above illuminates the surgical scene in such a way that the surface scaters the light and an interference patern - speckle pattern - is generated on the sensor. The speckle patern remains constant for stationary objects while moving particles in the scene result in varying interference thereby allowing the software to identify flowing blood. Software image processing is used to highlight areas of the scene with greater velocity (such as blood flowing through a vessel). Atorney Docket No. 58496-0002W01

[0170] Image Display: The LE produces a perfusion view that depicts the regions of tissue that have higher blood flow and tissue perfusion. The resulting perfusion map can be hidden from the user ((1) standby mode) or shown to the user ((2) perfusion view mode or (3) overlay mode). When the overlay is enabled, the standard third- party laparoscopic color image is shown with an overlay of the perfusion data. Video generated by the LE in either of the three modes can be visualized on a medical-grade surgical monitor connected to the Video out port of the LE.

[0171] Methods of using a combination of Dye-based and Dye-free visualization

[0172] In certain embodiments of the methods described herein, visualization before, during, or after an ablative process can help the success of the ablative process. In some embodiments, visualization can use a combination of dye-free or dye-based modalities. As noted above, ablation of prostate tissue can be via a transurethral, transperineal, transabdominal, or transrectal approach whereby the dye free or dye based method of visualization is endoscopic (cystoscopic) or transurethral.

[0173] Triphasic endoscopic (cystoscopic) visualization of submucosal tissue perfusion utilizing white light / dye free (laser speckle) / dye based (ICG) modalities allows real time feedback on ablation technologies such as water vapor during a transurethral approach. Utilizing white light and dye-free modalities to plan and treat BPH or other prostate disease tissue (such as cancer) or diseases within the bladder or renal collecting system, perfusion or the lack of perfusion can be used to improve ablation in real time. The superficial submucosal perfusion seen with the dye free system is not entirely adequate to determine tissue ablation and so deeper visualization will also be needed. The administration of ICG (dye-based) with subsequent endoscopic visualization will assess the tissue at a deeper submucosal level and allow- a comprehensive evaluation of tissue ablation or elimination of perfusion to the tissue. Use of both modalities are better than white light visualization and are complementary to each other in determining tissue perfusion. White light can be used to visualize blanching of the urothelium when tissue is ablated and show that perfusion of the tissue has stopped. Perfused tissue has a pink surface, whereas nonperfused tissue has a white / blanched surface. How ever, white light visualization does not reveal the entire degree of perfusion disruption or tissue ablation. There are superficial blood vessels that are not obvious to the naked eye under white light and Atorney Docket No. 58496-0002W01 so superficial dye free detection with laser speckle would be beneficial. Also, with laser speckle, this visualization can be quantitative rather than the qualitative nature of white light. Prostate tissue is not homogeneous within the same prostate or between different patients. This limits the reliability of water vapor (or other energy sources) in the ablation of benign prostatic hyperplastic tissue, so if the effectiveness of prostate tissue ablation is found lacking there is a great need to monitor tissue destruction in real time so that adjustments can be made. Dye-free or laser speckle methods do not require the administration of a compound so there is no need for an IV and no potential allergy to the dye. However, since it can only penetrate tissue a few mM deep, a more comprehensive method of deeper tissue destruction is preferably added. This is where dye based / ICG methods for administrating these compounds intravenously and then detection of signal or lack of signal can also give the surgeon real time feedback on tissue ablation efficacy. It is not obvious to combine these phases together in a transurethral fashion since all transurethral surgery has been done under white light and there has been no need to assess tissue ablation with the prostatic urethral mucosa intact. In addition, depending on the order these phases are used, they can be complementary to each other and together, better than white light.

[0174] Systems of Treating a Urological Organ / Tissue

[0175] Also provided herein are systems for treating a urological organ or tissue (for example, a prostate, bladder, kidney, ureter, or urethra). In some embodiments, the system can include a visualization system for trans -urethral delivery into a bladder, kidney, ureter, or urethra collecting system (as described herein) to guide a mucosal or non-mucosal disrupting ablation system (as described herein).

[0176] EXAMPLES

[0177] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0178] Outline for Examples below:

[0179] Applicable for the examples described below: there are various permutations with the three stages of the procedure while there can be multiple visualization phases involved in each stage. The phases involved are 1) White light 2) Dye Free / Laser speckle 3) Dye based or dependent / ICG. The first stage is "mapping baseline (MB)” Atorney Docket No. 58496-0002W01 of the prostatic urethra (treatment area) to get readings in treatment and non-treatment areas. The second stage is the "‘treatment guidance of prostate (TG) ' by the different modalities. The third stage is the “assessment of efficacy of treatment (AE)” and potential re-treatment.

[0180] Example 1:

[0181] In this example, the general protocol was: MB Stage with Biphasic visualization (white light and laser speckle) with cystoscope and then switch to treatment handpiece for TG stage with Biphasic Ablation (white light / laser speckle) with AE Stage Triphasic Visualization (white light / laser speckle / ICG) was assessed.

[0182] Triphasic endoscopic (cystoscopic) visualization of submucosal tissue perfusion utilizing white light / dye free (laser speckle) was used to help guide ablation of the prostate using a water vapor system. First, a cystoscope was inserted into the urethra, the prostatic urethra perfusion was visualized with white light and dye free / laser speckle for mapping baseline (MB) stage. A positive reading on the laser speckle was then performed on various areas of the prostatic urethra, either in the treatment fields (lateral lobes, median lobe, prostatic floor) or outside of the treatment field- verumontanum, external sphincter, and bladder neck (FIG. 2). Next, the treatment guidance stage (TG) under white light and laser speckle, a sterile needle treatment device replaced the cystoscope and this injected water vapor into the peri -urethral benign prostatic hyperplastic prostate tissue. The pre-treatment laser speckle reading was noted and then the steam was released for 8-9 seconds. Initially, the steam was visualized on white light and in the picture in picture, the steam movement is seen on laser speckle (FIG. 3). After the treatment, the superficial perfusion as seen with white light was evaluated from pink to white blanching. Next, the laser speckle quantitative number is seen to decrease from pre treatment levels to post treatment levels. Based on the visualization obtained from the laser speckle, the needle carry ing the water vapor was then guided to the correct tissue areas for treatment if there was still a substantial amount of superficial perfusion. This can be discordant with the white light visualization of perfusion. The final phase of assessment of efficacy (AE) stage then commences with the third phase of visualization (dye based) for deeper perfusion visualization. The patient was then intravenously administered 2.5mg / ml (a total of 5mg in a volume of 2ml saline solution). With standard dosages on a detection limit Atorney Docket No. 58496-0002W01 of "2 bars” of the ICG sensor (lowest ICG sensor without autofluorescence of the equipment), we saw ICG perfusion in the prostate within 30-50 seconds. (Figure 4). It took approximately 10-15 minutes for the ICG to clear on the low sensitivity setting of 2 bars. The areas that w ere treated were then monitored visually to see if there w as any perfusion with ICG. If ICG appeared in any of the treated areas, that would mean that there was still blood flow and the tissue was still viable (FIG. 5). Therefore, those areas were re-treated to ablate the viable tissue (FIG. 6). The entire visualization with white light, dye free / laser speckle and dye based / ICG was then repeated after treatment to ensure adequate destruction of tissue perfusion (FIG. 7).

[0183] Example 2:

[0184] In this example, micro-dosing of ICG was assessed to see the effect on clearance of ICG from a patient’s prostate tissue. The same protocol as described in Example 1 was utilized here. We then used dosages of 1 : 10, 1:50, 1: 100, and 1: 1000 dilution to determine perfusion and timing characteristics to optimize visualization (Figure 4). The areas that were treated w ere then monitored visually to see if there w as any perfusion with ICG. If ICG appeared in any of the treated areas, that would mean that there w as still blood flow and the tissue w as still viable (FIG. 5). Therefore, those areas were re-treated to ablate the viable tissue (FIG. 6). The entire visualization with white light, dye free / laser speckle and dye based / ICG was then repeated after treatment to ensure adequate destruction of tissue perfusion (FIG. 7).

[0185] Example 3:

[0186] In this example, the general protocol was: MB Stage Triphasic visualization with cystoscope and then switch to treatment handpiece for TG Stage biphasic visualization guided ablation and then AE Stage triphasic post treatment visualization.

[0187] A triphasic endoscopic (cystoscopic) visualization of submucosal tissue perfusion utilizing white light / dye free (laser speckle) / dye based (ICG) was used to help guide ablation of the prostate using a water vapor ablation system. During the MB stage, first, a cystoscope was inserted through the urethra, the prostatic urethra perfusion w as visualized with white light and dye free / laser speckle. A positive reading on the laser speckle was then performed on various areas of the prostatic urethra, either in the treatment fields (lateral lobes, median lobe, prostatic floor) or Atorney Docket No. 58496-0002W01 outside of the treatment field- verumontanum, external sphincter, and bladder neck. Next. ICG was given at Standard Dosage or a diluted dosage and visualized (lowest ICG sensor without autofluorescence) to map out the prostatic urethra as done with the prior white light and dye free / laser speckle modality. After time was allotted for the ICG to be cleared by the perfusion (usually 10-15 minutes), the ablative treatment was started. The TG stage starts under white light and laser speckle, a sterile needle treatment device replaces the cystoscope and this injects water vapor into the periurethral benign prostatic hyperplastic prostate tissue. The pre-treatment laser speckle reading was noted and then the steam was released for 8-9 seconds. Initially, the steam is visualized on white light and in the picture in picture, the steam movement is seen on laser speckle. After the treatment, the superficial perfusion as seen with white light is evaluated from pink to white blanching. Next, the laser speckle quantitative number is seen to decrease from pre treatment levels to post treatment levels. Based on the visualization obtained from the laser speckle, the needle carry ing the water vapor was then guided to the correct tissue areas for treatment if there was still a substantial amount of superficial perfusion. This can sometimes be discordant with the white light visualization of perfusion. The final stage AE of the procedure starts with the third phase of post treatment visualization is then started for deeper perfusion visualization. The patient was then intravenously administered 2.5mg / ml (a total of 5mg in a volume of 2ml saline solution) or a dilution thereof. The areas that were treated were then monitored visually to see if there was any perfusion with ICG. If ICG appears in any of the treated areas, that would mean that there was still blood flow and the tissue was still viable. Therefore, those areas were re-treated to ablate the viable tissue while monitoring superficial perfusion. The entire visualization with white light, dye free / laser speckle and dye based / ICG was then repeated after treatment to ensure adequate destruction of tissue perfusion.

[0188] Example 4:

[0189] In this example, the general protocol was: MB Stage with Triphasic visualization with cystoscope and then switch to treatment handpiece for TG Stage Triphasic visualization and AE Triphasic post treatment visualization.

[0190] A triphasic endoscopic (cystoscopic) visualization of submucosal tissue perfusion utilizing white light / dye free (laser speckle) / dye based (ICG) was used to Atorney Docket No. 58496-0002W01 help guide ablation of the prostate using a water vapor ablation system. During the MB stage of the procedure, a cystoscope was inserted into the urethra, the prostatic urethra perfusion was visualized with white light and dye free / laser speckle. A positive reading on the laser speckle was then performed on various areas of the prostatic urethra, either in the treatment fields (lateral lobes, median lobe, prostatic floor) or outside of the treatment field- verumontanum, external sphincter, and bladder neck. Next, ICG was given at standard dosage or a diluted dosage and visualized (lowest ICG sensor without autofluorescence) to map out the prostatic urethra as done with the prior white light and dye free / laser speckle modality. The TG stage was started by alternating between all three phases (white light, dye free, and dye based), the ablative treatment was started. Steam was injected into the periurethral benign prostatic hyperplastic prostate tissue. The pre-treatment laser speckle reading was noted and then the steam was released for 8-9 seconds. Initially, the steam is visualized on white light and in the picture in picture, the steam movement is seen on laser speckle. After the treatment, the superficial perfusion as seen with white light is evaluated from pink to white blanching. Next, the laser speckle quantitative number is seen to decrease from pre treatment levels to post treatment levels. Next, the dye based ICG phase was used to evaluate the clearance of ICG. In areas of treatment where the perfusion has been disrupted, the ICG will remain stagnant and hence a positive signal will result. However, after time for clearance, any of the areas where the ICG signal has disappeared, this means that perfusion is intact which has cleared the ICG dye. It would be in these “dark” areas where the ICG has cleared that would need re-treatment. Both the dye free / laser speckle and dye based / ICG can be discordant with the white light visualization of perfusion. Once the treatment has been guided in all three phases, the assessment of efficacy (AE) stage can be done with all three phases. After adequate time has elapsed 10-15 min when the ICG signal has diminished, the AE phase of visualization with white light, dye free / laser speckle and dye based / ICG was then repeated after treatment to ensure adequate destruction of tissue perfusion. Atorney Docket No. 58496-0002W01

[0191] Example 5:

[0192] In this example, rather than use a rigid cystoscope, the first step is to start with the Water Vapor Ablation Treatment devices. MB, TG, and AE Stage with White light and dye based / ICG.

[0193] In this example, the MB stage will utilize a biphasic visualization of submucosal tissue perfusion utilizing white light / dye based (ICG) was used to help guide ablation of the prostate using a water vapor ablation system. During the MB stage, the water vapor ablation device was inserted into the urethra, the prostatic urethra perfusion was visualized with white light and dye based / ICG phases after ICG was given at standard dosage or a diluted dosage and visualized (lowest ICG sensor without autofluorescence) to map out the prostatic urethra. A positive reading on the ICG was then performed on various areas of the prostatic urethra, either in the treatment fields (lateral lobes, median lobe, prostatic floor) or outside of the treatment field- verumontanum, external sphincter, and bladder neck. Next the TG Stage is started by alternating between all two phases (white light and dye based), the ablative treatment was started. Steam was injected into the peri-urethral benign prostatic hyperplastic prostate tissue. The pre-treatment white light and ICG reading was noted and then the steam was released for 8-9 seconds. Initially, the steam is visualized on white light and in the picture in picture, the ICG signal is seen. After the treatment, the superficial perfusion as seen with white light is evaluated from pink to white blanching. Next, the ICG signal intensity is monitored and with time, the areas where perfusion is still intact will start to see clearance of the ICG. This usually happens within 10-15 minutes. Next, the dye based ICG phase was used to evaluate the clearance of ICG. In areas of treatment where the perfusion has been disrupted, the ICG will remain stagnant and hence a positive signal will result. However, after time for clearance, any of the areas w here the ICG signal has disappeared, this means that perfusion is intact which has cleared the ICG dye. It w ould be in these “dark” areas where the ICG has cleared that would need re-treatment. The dye based / ICG signal can be discordant with the white light visualization of perfusion since it represents a deeper tissue destruction. Once the treatment has been guided in the two phases, the assessment of efficacy (AE) stage can be done with the tw o phases. After adequate time has elapsed 10-15 min when the ICG signal has diminished, the AE phase of Atorney Docket No. 58496-0002W01 visualization with white light and dye / ICG was then repeated after treatment to ensure adequate destruction of tissue perfusion.

[0194] A typical operative procedure is described as follows: when a patient who has failed medical therapy and has undergone urodynamic studies and shows obstructed voiding, an ablation procedure is the recommended course of action. Here, the patient elected a water vapor ablation of prostate tissue (also referred to as the REZUM treatment). The patient came to the operating room, prepped and draped in the usual sterile fashion after adequate induction of anesthesia and infusion of IV antibiotics. Subsequently, the REZUM handpiece was inserted under direct vision and the perfusion visualization system was engaged to look at superficial perfusion with LSI. The treatment was dictated by the usual REZUM protocol (1 cm gaps for steam treatment) but confirmed with the superficial perfusion scan. The prostatic urethra was measured with the handpiece scope from the bladder neck to the verumontanum. The lateral lobes were treated, starting at 1 cm distal to the bladder neck and progressing every’ 1 cm until the verumontanum was reached. Each treatment was 9 sec in length with a 2 sec pause afterwards. Next 1 ml of a 2.5 mg / ml concentration of ICG was given intravenously with a 10 ml bolus chaser. The prostate appeared to become infused with ICG in 30-60 seconds and this disappeared within 10-15 min (setting of 2-3 gain on ICG mode). Areas of active ICG positivity were then also examined with superficial perfusion. A decision w as then made to treat the areas of positive ICG infusion. Next, a repeat ICG bolus was given and re-treatment was then done on each side. In some cases, alternatively, only one prostate lobe is treated initially and then ICG bolus is given and the treated side is inspected with the nontreated side as a reference. Then missed areas of treatment (perfused areas) are retreated along with the contralateral side. A second ICG bolus was then given to reassess and re-treat the perfused periurethral prostate tissue (see, e.g., FIG. 14).

[0195] Example 6:

[0196] Transperineal ablation of prostate tissue with peri-urethral monitoring of tissue ablation and perfusion.

[0197] The patient will be placed in dorsal lithotomy position either under local or general anesthesia whereby a rigid or flexible cystoscope (FIGs. 8 and 9) will be inserted transurethrally to monitor the prostatic urethral fossa. Using dye based and or Atorney Docket No. 58496-0002W01 dye free perfusion visualization, the peri urethral tissue will be monitored as the transperineal ablative technology is employed. This can be microwave, laser, irreversible electroporation, or cryoablation (FIG. 10). For high intensity focused ultrasound, the ablative approach would be transrectal. FIG. 11 outlines the different approaches to the prostate for ablative technology.

[0198] Example 7: Focal Ablation of the prostate (Cryoablation) with Laser Speckle and ICG Visualization (Fluorescein Angiography)

[0199] The following describes the evaluation of urethral integrity through perfusion analysis after percutaneous ablation of prostate tissue. There are many modalities to ablate prostate tissue percutaneously. The energy used may damage the urethra and there are methods to protect the urethra mucosa and surround tissue. It is hard to assess urethral viability with white light. Therefore, before and after percutaneous ablation of prostate tissue, cystoscopy can be done to evaluate blood flow in the urethra in order to document urethra viability after treatment. If the blood flow is compromised by the ablation modality, there could be tissue extrusion and ultimately scar and stricture.

[0200] A patient who presented initially with an elevated PSA was worked up with MRI (magnetic resonance imaging) and biopsies of the prostate which revealed the location and aggressiveness of his prostate cancer. The patient was then counseled on all the options. The patient elected to undergo focal ablation of the prostate (Cryoablation). The patient w as prepped and draped in the usual sterile fashion after adequate induction of anesthesia and infusion of IV antibiotics, and a proper timeout was performed. Briefly, the transrectal probe was placed after the 16 Fr foley was inserted. The scrotum was secured with towel clips. The prostate was subsequently sized, and a grid w as put on. Good symmetry w as observed, and the rectal wall was identified along with the seminal vesicles. In addition, the balloon at the bladder neck was also visualized. Initially, the Chiba needle was inserted between the plane of Dennovilhers's fascia and the rectal wall. Next 20 to 40 mis of normal saline was infiltrated in this plane from the seminal vesicles to the apex. This allowed separation between the prostate capsule and the rectum as well as the apex from the external sphincter with this hydrocushion. The prostate lesion was now7mapped out and cryoablation needles were placed to cover the lesion with a 5 mM margin. Great care Atorney Docket No. 58496-0002W01 was taken to prevent the ice ball from damaging the urethra, sphincter, or rectum. In addition, we placed 2 temperature sensors, one was at the external sphincter and another one was placed within the treatment area. We were able to see the delineation between the rectum and the lower aspect of the prostate, going along Denonvilliers fascia. We did subsequently take the old catheter out and we utilized a flexible cystoscope to visualize (under white light) the entire urethra, prostatic urethra, and the bladder and no needles were seen in the bladder or in the urethra.

[0201] At this time then, 1 ml of ICG (2.5 mg / ml) was given IV and the entire lower urinary7tract was visualized with the laser speckle and ICG mode. There appeared to be adequate perfusion of the prostatic urethra with both superficial and deep perfusion (see, FIG. 15- this is the mapping baseline).

[0202] The Amplatz Super Stiff wire was put into the bladder, and the urethral warmer was placed over the Super Stiff wire and kept the urethra warm. At this time, we then cryoablated the entire prostate lesion area(s) starting with the anterior row and progressing to the posterior row. The ablative lesion temperature probe was in the freezing temperature range that was adequate for cell death while the external urinary sphincter temperature probe was in the appropriate tissue preservation range during the entire procedure. There was then an active thaw and then the second freeze was started. It did appear that there was a good freeze within the lesion of interest w ith a 5 mM margin. The patient did tolerate the entire procedure. The urethral warmer was removed and the flexible cystoscope was placed under direct vision into the urethra and the mucosa was visualized again with laser speckle and ICG after a 1 ml of ICG (2.5 mg / ml) was given. Confirmation was seen for adequate blood flow in the prostatic urethra after cryoablation of the prostate (see, FIG. 15- this the efficacy assessment.

[0203] Example 8: Bladder Cancer / Tumors

[0204] Described in examples 8-12 is the detection and ablation monitoring of bladder, ureter, and the renal collecting system with dye free and dye-based perfusion systems. The flexible or rigid cystoscope or ureteroscope can be used to viewperfusion within the bladder, ureter, and renal collecting system for a mapping baseline or diagnostic. The ablation system can be transluminal or transabdominal or transperineal to ablate tissue and allow' perfusion monitoring with either a laser, Atorney Docket No. 58496-0002W01 cryoablation, microwave, electroporation, or transluminal removal devices such as cold cup or electrical resectascopes. Figure 12 shows a dye free / laser speckle imaging of superficial perfusion within the bladder submucosa. Dye bases / ICG can also be visualized in a similar fashion. It is postulated (shown) that ureteral and renal collecting system perfusion can be transluminally visualized in a similar fashion.

[0205] The bladder has a very robust blood supply bilaterally from the internal iliac arteries. Its main purpose is for storage and expelling of urine. There are many disease states of the bladder that would be detected with angiography. The blood vessel pattern of the tumors is different than normal urothelium in pattern, quantity, and enhancement. These masses could be detected at an earlier state than with white light. The angiography can then be used to guide removal or ablation (TG- treatment guidance) and can then also be used to monitor healing (AE- Assessment of Efficacy).

[0206] A patient, who had a recent cystoscopy or imaging and was found to have suspicious bladder lesions was counseled to undergo cystoscopy and have the bladder lesion removed in the operating room. The patient was prepped and draped in the usual sterile fashion after adequate induction of anesthesia and infusion of IV antibiotics and a proper timeout. The cystoscope was placed under direct vision into the bladder. The bladder masses were seen and evaluated with LSI (FIG. 16), and ICG (FIG. 17; MB stage) infusion. Then using the cold cup biopsy forceps the lesions w ere removed (TG) and the base was fulgurated (FIG. 17; AE).

[0207] Example 9: Urethral Stricture

[0208] The urethra has a dual blood supply from proximal and distal arterial sources. It is short in the woman and is the length of the penis in the man. Stricture is a chronic inflammation of the mucosal surface that leads to fibrosis and lack of blood flow. On white light, this is usually seen as a white scar. However, with ICG angiography, the exact extent of vasculature (which is usually more deficient than the white light visual-MB)) can be determined. This can give guidance on where to dilate (with balloon or instrument) or excise (with laser or cold knife) the stricture (TG). In addition, it may be used to track the healing process after treatment (AE). There are also benign and malignant masses of the urethra w hich can be visualized with ICG. The blood vessel pattern of the tumors is different than normal urothelium in pattern, quantity, and enhancement. These masses could be detected at an earlier state than Atorney Docket No. 58496-0002W01 with white light. Then the angiography can be used to guide removal or ablation and then also used to monitor healing.

[0209] The patient presented with hematuria or difficulty urinating and upon cystoscopy with white light, the patient was found to have either a bladder neck or urethral stricture. The patient was then counseled on treatment of the stricture in the office or operating room. Using either a flexible or rigid cystoscope, the urethra was visualized under white light. LSI, and after ICG infusion (FIG. 18). This allowed the visualization of the extent of the stricture and guide treatment (FIG. 19). In addition, the bladder neck was evaluated with white light, LSI, and ICG and treatment was guided (FIG. 20).

[0210] Example 10: Ureteral Stricture

[0211] The ureter has a triplicate blood supply from proximal (renal) to mid (from the retroperitoneal vessels) and distal (bladder) arterial sources. Its main function is to use peristalsis to move filtered ureter down into the bladder. Stricture is a chronic inflammation of the mucosal surface that leads to fibrosis and lack of blood flow. On white light, this is usually seen as a white scar. However, with ICG angiography, the exact extent of vasculature (which is usually more widespread than the white light visual) can be determined (MB). This can give guidance (TG) on where to dilate or excise the stricture. In addition, it can be used to track the healing process after treatment (AE). There are also benign and malignant masses of the urethra which can be visualized with ICG. The blood vessel pattern of the tumors is different than normal urothelium in pattern, quantity, and enhancement. These masses could be detected at an earlier state than with white light (MB). Then the angiography can be used to guide (TG) removal or ablation and then also used to monitor healing (AE).

[0212] The patient presented with hydronephrosis due to the obstructed ureter from the stricture. The patient was imaged with intravenous contrast and found to have a ureteral stricture. The stricture was then dilated and a stent was placed to un-obstruct the ureter. This was allowed to heal, and the patient was taken back to the operating room. The left stent was removed and ureteroscopy was done. Briefly, the patient was prepped and draped in the usual sterile fashion after adequate induction of anesthesia, infusion of IV antibiotics, and a proper timeout was performed. Written consent obtained. The bladder was entered and the ureteral orifice was visualized, and the Atorney Docket No. 58496-0002W01 stent was removed. A wire was placed through the stent and seen to curl in the upper tract. The semirigid or flexible ureteroscope was then placed up the ureter alongside or over the wire. The ureter was then visualized with white light, LSI (FIG. 21), and ICG (FIG. 22). As the stricture was approached, the perfusion diminished (FIG. 23) until the stricture was visualized. Laser speckle and ICG infusion was used to visualize superficial and deeper perfusion (FIG. 24). No tumor was seen, and the stricture appeared to be dilated sufficiently with good blood flow around the stricture. If the stricture was still there with inadequate perfusion, then options of using a balloon to dilate or using an ablative technology' to incise the stricture could be done and assessment after treatment done with the same perfusion visualization system.

[0213] Example 11: Ureteral Tumor

[0214] The ureter has a triplicate blood supply from proximal (renal) to mid (from the retroperitoneal vessels) and distal (bladder) arterial sources. Its main function is to use peristalsis to move filtered ureter down into the bladder. There can be malignant or benign masses which can be detected earlier with angiography. The blood vessel pattern of the tumors is different than normal urothelium in pattern, quantity, and enhancement. These masses could be detected at an earlier state than with white light. Then the angiography can be used to guide removal or ablation and then also used to monitor healing.

[0215] A patient who presented with imaging that show ed a narrow' distal left ureter or mass with left hydronephrosis was brought to the operating room and a retrograde pyelogram was shot that confirmed this narrowing. Then the area was dilated and a stent was placed. Alternatively, a stent is not placed but ureteroscopy is done instead as the initial evaluation. In this case, a stent was placed, the patient returned to have the stent removed and the area of stricture w as evaluated by white light, laser speckle (LSI) and Indigo Cyanine Green (ICG) fluorescence. The patient came back for definitive treatment and was prepped and draped in the usual sterile fashion after adequate induction of anesthesia, infusion of IV antibiotics, and a proper timeout was performed. The bladder was entered and the left ureteral stent was pulled out to the meatus. The wire w as then used to cannulate the stent. The stent w as removed and the wire was left in place. A semi rigid ureteroscope was then placed alongside the wire and the ureter was visualized under white light as well as LSI and ICG (FIG. 21 and Atorney Docket No. 58496-0002W01

[0216] 22 MB). There was a mass at the area in question and biopsies were taken (TG) from the area and sent to pathology (FIG. 25). The area was then re-visualized during and after the biopsy with ICG (FIG. 26 AE).

[0217] Example 12: Renal collecting system

[0218] The collecting system of the kidneys have the same vascular supply as the kidney. Its main purpose is to collect the filtered urine and allow it to pass down the ureter into the bladder. There can be stricture as well as tumors (benign or malignant). Stricture is a chronic inflammation of the mucosal surface that leads to fibrosis and lack of blood flow. On white light, this is usually seen as a white scar. However, with ICG angiography, the exact extent of vasculature (which is usually different than the white light visual) can be determined. This can give guidance on where to dilate or excise the stricture. In addition, it may be used to track the healing process after treatment. The blood vessel pattern of the tumors is different than normal urothelium in pattern, quantity, and enhancement. These masses could be detected at an earlier state than with white light. Then the angiography can be used to guide removal or ablation and then also used to monitor healing.

[0219] A patient who presented with imaging that showed a renal collecting system with hydronephrosis was brought to the operating room and the bladder was entered with a rigid cystoscope and the ureteral orifice was identified. A retrograde py elogram was shot that confirmed that a filling defect was in the upper tract. A wire was then used to be placed up into the renal pelvis. Next, a ureteral access sheath was then placed over the wire to the proximal ureter and then used to place the fiberoptic flexible ureteroscope up into the kidney for further inspection of the kidney. Again, the upper ureter and renal collecting system were then inspected under white light, LSI (FIG. 27) and ICG (FIG. 28). The flexible ureteroscope was then retroflexed to visualize the entire renal pelvis (FIG. 29). Masses found using this triphasic visualization were ablated or biopsied under guidance and assessed for efficacy.

[0220] Example 13:

[0221] Abstract for initial feasibility and studies with BPH prostate ablation and short term follow up. Atorney Docket No. 58496-0002W01

[0222] REZUM™ is a BPH water vapor treatment done in the operating room or office. Treatment degree is unpredictable: results are inconsistent due to differences in prostate tissue consistency and inconsistent areas of treatment. We propose that realtime tissue perfusion monitoring during REZUM treatment will result in more consistent outcomes. ActivSight™ connects between a standard surgical camera and scope. It measures tissue perfusion through two complimentary advanced imaging modalities: indocyanine green fluorescence angiography (ICG-FA) and laser speckle contrast imaging (LSCI). Results are displayed to the surgeon as a real-time color heatmap, overlaid on the surgical video, indicating the degree of tissue perfusion.

[0223] A single surgeon’s experience was retrospectively reviewed. 13 patients consented to the addition of ActivSight™ and treatment was guided by real time perfusion status. We documented imaging of the treatment and intra-operative decision making based on the presence or absence of perfusion, with short-term safety and efficacy follow up.

[0224] 13 patients underwent REZUM with ActivSight™: 11 in the operating room (OR) included ICG-FA and LSCI perfusion monitoring, 2 in the office with only LSCI. Follow up ranged from 1 to 12 weeks. One patient was excluded due to failure of a trial of void.

[0225] Pre-op averages', age at treatment 65 yo (Range 48-83), IPSS 23.8 (4-30), QOL 4.5 (2-6). and PVR 84 mL (0-500), prostatic urethral length 3.5 cm (1.5-6.0). number of treatments 7.8 (4-15).

[0226] Post-op averages: IPSS 15 (2-25), QOL 3.14 (1-6), PVR 36 mL (0-131).

[0227] LSCI for superficial perfusion gave both quantitative and qualitative data feedback in real time. As the treatment progressed, treated tissue perfusion decreased. When ICG was infused, most of the signal was seen within one minute and washed out within 10 minutes. Infusion after the treatment showed areas of suboptimal treatment that needed additional water vapor or showed adequate tissue treatment.

[0228] Cystoscopy images at 3 months showed defects consistent with adequate treatment.

[0229] Figures 30 and 31 showed the data of water vapor treatment alone in a dot plot and bar graph of IPSS, voided volume, max flow, and average flow. A p value was generated with the before and after treatments. FIG. 32 showed the addition of targeted triphasic visualization to the vapor treatment at 3 months for IPSS and Atorney Docket No. 58496-0002W01 volume voided. FIG. 33 showed the same patients with post void residual and flow time. Finally. FIG. 34 showed the same patients with average and maximal flow rates. All of this is summarized with p values in the first two rows of the table in FIG. 35.

[0230] Data from patients at 6 months have been tabulated and reported. Specifically, prostate ablation with vapor alone versus targeted prostate ablation with vapor and triphasic visualization is shown in FIG. 36 (six Month outcomes on urinary function as reflected by patient’s questionnaire) and FIG. 37 (urodynamic parameters data).

[0231] Comparison shows the addition of targeted triphasic visualization has a more significant p-value of IPSS number decrease (International Prostate Symptom Score) and quality of life that the patient (p=0.017 v p = 0.000024). These symptom scores are maintained at 6 months while the PVR also improved to p=0.22. (FIG. 32 last row of table).

[0232] Urodynamic studies before (FIG. 38) and 1 year after (FIG. 39) targeted prostate ablation with vapor and triphasic visualization shows that overall, the voiding pattern before was in the obstructive region while afterwards, the pattern is in the equivocal and non-obstructive region. Also, in the graph the detrusor contraction before was much higher and needing more pressure than after the treatment.

[0233] In addition, urodynamics is done to test the patient’s urinary' function which revealed that the patient's flow time and post void residual (PVR) have diminished while their urine flow and bladder capacity have increased. All of these changes reflect the significant advantage of using the triphasic visualization to clear more prostate tissue for better results as reported by the patient and as reflected in testing.

[0234] 1 year follow up will have all the clinical data gathered and compared with a similar cohort of patients that did not have the target triphasic system employed.

[0235] OTHER EMBODIMENTS

[0236] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, w hich is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Atorney Docket No. 58496-0002W01WHAT IS CLAIMED IS:

1. A method for treating a prostate, bladder, kidney, ureter, or urethra of a patient, comprising the steps of: inserting a perfusion visualization system into a bladder, kidney, ureter, or urethra of the patient; inserting a non-mucosal-disrupting ablation system into the patient, ablating a portion of a prostate, bladder, kidney, ureter, or urethra of the patient using the non-mucosal-disrupting ablation system; and using the perfusion visualization system to detect perfusion or lack of perfusion in real time in the prostate, bladder, kidney, ureter, or urethra to determine efficacy of the ablating step based on the visualization system; and stopping or continuing treatment according to the perfusion or lack of perfusion seen in real time.

2. The method of claim 1, wherein the perfusion visualization system is delivered trans-urethrally.

3. The method of claim 2, wherein the visualization system is an endoscope or a cystoscope. preferably a flexible or rigid cystoscope, or a flexible or rigid ureteroscope.

4. The method of claim 1, wherein using the perfusion visualization system comprises detecting a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

5. The method of claim 4, wherein using the visualization system comprises detecting a combination of both a dye-based reagent and a dye-free tool.

6. The method of claim 5, wherein the dye-free tool is laser speckle.

7. The method of claim 5, further comprising intravenously administering the dye-based reagent to the patient.Atorney Docket No. 58496-0002W018. The method of claim 7, wherein the dye-based reagent is administered immediately before or immediately after the ablating step.

9. The method of claim 8, wherein the dye-based reagent is administered 30 seconds to 30 minutes prior to the ablating step.

10. The method of claim 8. wherein the dye-based reagent is administered 30 seconds to 30 minutes after the ablating step.

11. The method of any one of claims 7 to 10, wherein the dye-based reagent appears in the prostate, bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of administering the dye-based reagent to the patient, and the perfusion visualization system is used to detect perfusion or lack of perfusion in real time in the prostate, bladder, kidney, ureter, or urethra within 15 seconds to 5 minutes of the administration.12 The method of any one of claims 7 to 11, wherein the dye-based reagent clears from the patient's prostate, bladder, kidney, ureter, or urethra within 10 minutes to 30 minutes of administering the dye-based reagent to the patient.

13. The method of any one of claims 7 to 12, wherein the dye-based reagent is indocyanine green (ICG) angiography, riboflavin, or fluoresceine.

14. The method of claim 13, wherein the dye is ICG.

15. The method of claim any one of claims 7 to 14, wherein the dye is administered to the patient at a concentration range of about 1 mg / ml to about 5 mg / ml.

16. The method of claim any one of claims 7 to 14, wherein the dose of the dye that is administered to the patient is about 0.5 to 10 mg, e.g., 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg. 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg. 9.5 mg, 10.0 mg (e.g., 5.0 mg).Attorney Docket No. 58496-0002W0117. The method of any one of claims 1 to 16, wherein the non-mucosal- disrupting ablation system is delivered trans-urethrally, trans-perineally, trans- abdominally, or trans-rectally.

18. The method of any one of claims 1 to 17, wherein the non-mucosal disrupting ablation system utilizes one of the following methods: water vapor / steam. laser, electroporation, cryoablation, high intensity focal ultrasound, or microwave methods.

19. The method of claim 18, wherein the non-mucosal disrupting ablation system is a water vapor / steam system and is delivered trans-urethrally.

20. The method of any one of the preceding claims, wherein the patient has benign prostatic hyperplasia or prostate cancer.

21. A system for ablating prostate, bladder, kidney, ureter, or urethra tissue, the system comprising: a visualization system for trans-urethral delivery into a bladder, kidney, ureter, or urethra collecting system, and anon-mucosal disrupting ablation system.

22. The system of claim 21, wherein the visualization system is an endoscope, a cystoscope, preferably a flexible or rigid cystoscope, or a flexible or rigid ureteroscope.

23. The system of claim 22, wherein the visualization system comprises using a dye-based reagent, a dye-free tool, or a combination of both a dye-based reagent and a dye-free tool.

24. The system of any one of claims 21 to 23, wherein the non-mucosal- disrupting ablation system utilizes one of the following methods: water vapor / steam, laser, electroporation, cryoablation, high intensity focal ultrasound, or microwave methods.Atorney Docket No. 58496-0002W0125. The system of any one of claims 21 to 24, wherein the non-mucosal- disrupting ablation system is for trans-urethral, trans-perineal, trans-abdominal, or trans-rectal delivery.

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