System, apparatus, and method for selectively insonating pancreatic cysts to image and assist targeted exfoliation of cells therefrom

Abstract

A cell collection system comprising an endoscope including: a probe configured to produce first ultrasound waves configured to image a target, wherein the system includes circuitry to control the first ultrasound waves; and selectively insonate a target in a bodily organ to assist in exfoliation of cells and / or fragments of the target, wherein the system includes circuitry to produce second ultrasound waves for the selective insonation.

Description

[0001] SYSTEM, APPARATUS, AND METHOD FOR SELECTIVELY INSONATING PANCREATIC

[0002] CYSTS TO IMAGE AND ASSIST TARGETED EXFOLIATION OF CELLS THEREFROM

[0003] RELATED APPLICATION / S

[0004] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 702,142, filed on October 1, 2024, the contents of which are incorporated herein by reference in their entirety.

[0005] FIELD OF THE INVENTION

[0006] The present invention, in some embodiments thereof, relates to the field of medical diagnostics and, more particularly, but not exclusively, to an apparatus and method for directing ultrasound waves to a target such as, for example, a cyst located within a pancreas, inducing exfoliation of target cells for collection, and collection of the exfoliated cells originating in the target.

[0007] BACKGROUND OF THE INVENTION

[0008] Pancreatic cancer is an extremely deadly cancer whose high mortality rate stems primarily from its tendency to be detected at an advanced stage. The absence of reliable and / or non-invasive tests for early detection of pancreatic cancer is responsible for its late detection. The majority of pancreatic cancers begin as pancreatic intraepithelial neoplasias (PanINs) - small lesions that, left untreated, may advance into pancreatic cancer. PanINs are not visible on imaging until they reach approximately l-2cm at which point they already have 100M cancer cells. A smaller subset of pancreatic cancers (around 10%) emanate from intraductal papillary mucinous neoplasms (IPMN). IPMNs are most often benign cysts, but in many cases, they are precursors to pancreatic cancer. It is estimated that 20% of IPMNs develop into Pancreatic ductal adenocarcinomas (PDAC).

[0009] Although IPMN accounts for only approximately 10% of PDACs, they are more readily visible on imaging (as a result of being filled with fluid) than PanINs. In fact, given the prevalence of IPMNs in non-symptomatic patients and high observation rates, combined with their relatively high conversion rate of about 20%, IPMNs are routinely surveilled by clinicians.

[0010] In fact, it is estimated that eight million Americans have a pancreatic cyst and only approximately 1.33 million of them are detected. Most often, IPMNs are detected incidentally on an MRI or CT Scan performed for reason unrelated to pancreatic disease.

[0011] Once an IPMN is detected, it is typically tested and followed by a physician. A common method of testing IPMNs is through endoscopic ultrasound examination during which ultrasound imaging is used to guide a fine needle aspiration (known as EUS-FNA) of the IPMN fluid. During the procedure, a fine needle is extended through the wall of the stomach and penetrates the pancreatic cyst to extract cyst fluid with the aim of retrieving any abnormal cells that may have shed into the cyst fluid.

[0012] It is known in the art that echoendoscopes are devices that are configured to combine conventional endoscopic visualization with high-resolution ultrasound imaging. In this regard, such devices include a flexible insertion tube, a control section with angulation control, suction / irrigation controls, and a cable that connects to external video and ultrasound processors. In addition, an ultrasound transducer is integrated at its distal tip. This allows physicians to directly visualize the mucosal surface while simultaneously generating real-time sonographic images of structures adjacent to the gastrointestinal tract, such as the pancreas, bile ducts, and lymph nodes. Known devices, which are configured for imaging, typically generate short ultrasound pulses such as (e.g. l-2us in length). In addition, such scopes commonly include a working channel through which a needle may be deployed to collect cells, for example, by fine-needle aspiration (FNA).

[0013] A device similar to a standard echoendoscope such as, for example, Olympus GF-UCT180, manufactured by Olympus America, Inc., of Center Valley, PA, USA, may be used in endoscopic visualization with high-resolution ultrasound imaging and collection of cells (FNA).

[0014] However, EUS-FNA has historically yielded a very low specimen adequacy rate (of less than 5%), because usually few or no pancreatic cells are found in the cyst fluid. Gastroenterologists, thus, have limited ability to adequately detect and monitor pre-cancer or cancer of the pancreas, and as such, there is a need in the art for a more accurate and reliable test for abnormal cells of IPMNs.

[0015] It is known to place an ultrasound probe in position to insonate an organ for imaging a cyst and breaking up targeted epithelial cells of the cyst, and biopsy for analysis of the cystic epithelial cells. For example, WO 2024 / 228202 teaches insonating a target tissue by ultrasound energy and producing cytopathologic cell samples. Ultrasound waves or beams are directed at the target tissue by an ultrasound inducer located outside the body. Such placement of the ultrasound inducer has the potential disadvantage of damaging surrounding blood vessels, nerves, and / or other structures. In some embodiments, the probe is introduced to a predetermined point near the prostate, optionally, introduced thereto rectally.

[0016] WO 2019 / 183623 teaches “obtaining enriched cell samples from an organ in a subject using an ultrasound contrast agent and insonating. Contiguous fragments of epithelia are obtained which are useful for subsequent histological analysis and for informing therapy and other medical considerations” (abstract). SUMMARY OF THE INVENTION

[0017] Embodiments of the invention provide an echoendoscope or similar device with an integrated ultrasound transducer that is additionally or alternatively configured to generate ultrasound energy configured to dislodge epithelial cells within pancreatic cysts.

[0018] According to an aspect of some embodiments of the present invention there is provided a cell collection system comprising an endoscope including: a probe configured to produce first ultrasound waves configured to image a target, wherein the system includes circuitry to control the first ultrasound waves; and selectively insonate a target in a bodily organ to assist in exfoliation of cells and / or fragments of the target, wherein the system includes circuitry to produce second ultrasound waves for the selective insonation.

[0019] According to some embodiments of the invention, the probe is configured to produce ultrasound pulses in a range of from 20-800 us.

[0020] According to some embodiments of the invention, the probe is configured to be inserted into a body to selectively insonate the target from inside the body.

[0021] According to some embodiments of the invention, the collection device is deployed from the endoscope while the endoscope is positioned inside a body.

[0022] According to some embodiments of the invention, the second ultrasound waves include at least one of: a plurality of higher intensity ultrasonic beams directed at the target; and at least one lower intensity, non-focused ultrasonic beam directed at the target.

[0023] According to some embodiments of the invention, the second ultrasound waves include at least one of: a plurality of higher intensity, focused ultrasonic beams directed at the target, wherein the higher intensity, focused ultrasonic beams have a Mechanical Index in a range of approximately 0.4 to 1.9; and at least one lower intensity, non-focused ultrasonic beam directed at the target, wherein the at least one lower intensity ultrasonic beam has a Mechanical Index of less than 0.4.

[0024] According to some embodiments of the invention, the second ultrasound waves include at least one of: a plurality of higher intensity, focused ultrasonic beams directed at the target, wherein the higher intensity, focused ultrasonic beams have a duration in a range of from 1-15 minutes; and at least one lower intensity, non-focused ultrasonic beam directed at the target, wherein the at least one lower intensity ultrasonic beam has a duration in a range of from 3-30 minutes. According to some embodiments of the invention, the second ultrasound waves are directed at the target to cause at least one of: the creation of breaks between cells and / or connections between cells of the epithelium of the target; and exfoliation of cells and / or fragments of the target.

[0025] According to some embodiments of the invention, the exfoliation of cells and / or fragments of the target is enhanced by the administration of a contrast agent into the target.

[0026] According to some embodiments of the invention, the contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

[0027] According to some embodiments of the invention, the bodily organ is selected from: a pancreas, a kidney, a liver, and an ovary.

[0028] According to some embodiments of the invention, the system includes a collecting device deployable to collect a sample originating from the target.

[0029] According to some embodiments of the invention, the at least one needle is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

[0030] According to some embodiments of the invention, the collecting device is a portion of the endoscope.

[0031] According to some embodiments of the invention, the collecting device is automatically deployable to collect the sample.

[0032] According to some embodiments of the invention, the bodily organ is a pancreas, and wherein the system is configured to automatically administer to the pancreas one of secretin and a bioequivalent of secretin, before deployment of the collecting device.

[0033] According to an aspect of some embodiments of the present invention there is provided a cell collection system including: an endoscope comprising a probe, wherein the system has at least one insonation mode in which the probe selectively directs ultrasound waves directed at a target in a bodily organ; a memory for recording data obtained by the imaging, in a recording mode; and a user interface for actuating operation of the probe and the memory; and circuitry for controlling operation of the endoscope and the probe, wherein the circuitry is configured to switch among the at least one insonation mode and the recording mode.

[0034] According to some embodiments of the invention, the system further includes a collection device for collecting a sample originating from the target, in a collecting mode; wherein the user interface is configured for actuating operation of the collection device; and wherein the circuitry is configured for controlling operation of the collection device.

[0035] According to some embodiments of the invention, the collection device is automatically actuated.

[0036] According to some embodiments of the invention, the user interface provides an indication as to which of the at least one insonation mode, the recording mode, and the collection mode is currently operational.

[0037] According to some embodiments of the invention, the collection device is at least one needle.

[0038] According to some embodiments of the invention, the at least one needle is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

[0039] According to some embodiments of the invention, the collection device is a portion of the endoscope.

[0040] According to some embodiments of the invention, the probe is configured to be inserted into a body to selectively insonate the target from inside the body.

[0041] According to some embodiments of the invention, the user interface provides an indication as to which of the at least one insonation mode and the recording mode is currently operational.

[0042] According to some embodiments of the invention, the at least one insonation mode includes: an imaging mode; and at least one of: a first insonation mode in which the probe directs a plurality of higher intensity, focused ultrasonic beams at the target; and a second insonation mode in which the probe directs at least one non-focused, lower intensity ultrasonic beam at the target.

[0043] According to some embodiments of the invention, the probe is configured to insonate the target in the first insonation mode, wherein the plurality of higher intensity, focused ultrasonic beams have a mechanical index in a range of from 0.4- 1.9.

[0044] According to some embodiments of the invention, the probe is configured to insonate the target in the second insonation mode, wherein the at least one non-focused ultrasonic beam has a Mechanical Index of less than 0.4.

[0045] According to some embodiments of the invention, the probe is configured to insonate the target in the first insonation mode, wherein the plurality of higher intensity, focused ultrasonic beams have a duration in a range of from 1-15 minutes. According to some embodiments of the invention, the probe is configured to insonate the target in the second insonation mode, wherein the at least one non-focused ultrasonic beam has a duration in a range of from 3-30 minutes.

[0046] According to some embodiments of the invention, at least one of the probe, the memory, and the collection device is automatically actuated.

[0047] According to an aspect of some embodiments of the present invention there is provided medical of use of a contrast material for cell collection from a target in a bodily organ, wherein the contrast material enhances at least one of: the breaking of cells and / or connections between cells of the target epithelium; and the exfoliation of cells and / or fragments of the target.

[0048] According to some embodiments of the invention, the contrast material is used in conjunction with insonation of the target to produce the enhancement.

[0049] According to some embodiments of the invention, the insonation includes at least one of: the direction of a plurality of higher intensity, focused ultrasonic beams at the target; and the direction of at least one wide, non-focused ultrasonic beam at the target.

[0050] According to some embodiments of the invention, the contrast material is administered concurrently with or after the direction of the at least one wide ultrasonic beam at the target.

[0051] According to some embodiments of the invention, the contrast material is configured to induce and / or assist in exfoliation of cystic cells and tissue fragments in the target.

[0052] According to some embodiments of the invention, the contrast material is configured to at least partially separate segmented epithelium of the target from a wall of the target.

[0053] According to some embodiments of the invention, the contrast material is selected from microbubbles, nanobubbles, and nanodroplets.

[0054] According to some embodiments of the invention, the contrast material is one of: infused through IV; and infused directly into the target.

[0055] According to an aspect of some embodiments of the present invention there is provided medical use of secretin or a bioequivalent of secretin for cell collection from a target in a pancreas, wherein the secretin is administered after insonation of the target to assist in exfoliation of cells and / or fragments of an epithelium of the target.

[0056] According to some embodiments of the invention, the insonation includes at least one of: the direction of a plurality of focused, higher intensity ultrasonic beams at the target; and the direction of at least one non-focused, lower intensity ultrasonic beam at the target. According to some embodiments of the invention, the secretin or a bioequivalent of secretin is administered one of: after the direction of the plurality of focused, higher intensity ultrasonic beams at the target; and prior to or concurrently with the direction of at least one non-focused, lower intensity ultrasonic beam at the target.

[0057] According to an aspect of some embodiments of the present invention there is provided a method of collecting a sample originating from a target in a bodily organ, the method comprising: insonating the target to assist in exfoliation of epithelial cells of the target; and collecting the sample originating from the target.

[0058] According to some embodiments of the invention, the insonating is selective insonating of the target.

[0059] According to some embodiments of the invention, the insonating includes: producing first ultrasound waves to image the target; and producing second ultrasound waves directed at the target, wherein the second ultrasound waves assist in the exfoliation of cells and / or fragments of the target.

[0060] According to some embodiments of the invention, the producing second ultrasound waves includes producing ultrasound pulses in a range of from 20-800 us.

[0061] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing a plurality of higher intensity, focused ultrasound beams at the target; and directing at least one lower intensity, non-focused ultrasound beam at the target.

[0062] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing at the target a plurality of higher intensity, focused ultrasound beams, having a Mechanical Index in a range of from 0.4- 1.9; and directing at the target at least one lower intensity, non-focused ultrasound beam having a Mechanical Index of less than 0.4.

[0063] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing at the target a plurality of higher intensity, focused ultrasound beams, having a duration in a range of from 1-15 minutes; and directing at the target at least one lower intensity, non-focused ultrasound beam having a duration in a range of from 3-30 minutes.

[0064] According to some embodiments of the invention, the second ultrasound waves cause at least one of: the breaking of cells and / or connections between cells of the epithelium of the target; and exfoliation of cells and / or fragments of the target.

[0065] According to some embodiments of the invention, the insonating the target includes inserting an ultrasound probe into a body and selectively insonating the target from inside the body.

[0066] According to some embodiments of the invention, the method further comprises delivering a contrast agent to the target.

[0067] According to some embodiments of the invention, the contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

[0068] According to some embodiments of the invention, the insonating includes directing at least one lower intensity, non-focused ultrasound beam at the target, concurrently with or before the delivering a contrast agent.

[0069] According to some embodiments of the invention, the delivering a contrast agent is performed by one of: delivering the contrast agent intravenously; and delivering contrast agent directly into the target.

[0070] According to some embodiments of the invention, the target is a pancreatic cyst, and wherein the sample is collected from one of: the target, a pancreatic duct, and a duodenum.

[0071] According to some embodiments of the invention, the collecting includes collecting a sample of at least one of fluid and cells originating from the target.

[0072] According to some embodiments of the invention, the collecting includes inserting at least one needle to collect the sample.

[0073] According to some embodiments of the invention, the at least one needle is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

[0074] According to some embodiments of the invention, the collecting includes collecting the sample from a pancreatic ampulla.

[0075] According to some embodiments of the invention, the collecting includes collecting the sample with a suction channel of an endoscope. According to some embodiments of the invention, the target is a pancreatic cyst, and wherein the collecting fluid includes administering secretin or a secretin bioequivalent to induce secretion of pancreatic juice.

[0076] According to some embodiments of the invention, the collecting pancreatic juice includes using a suction channel of an endoscope advanced into a duodenum, adjacent a pancreatic ampulla.

[0077] According to some embodiments of the invention, the collecting a sample includes collecting at least one of fluid, cells, and fragments originating from the target.

[0078] According to some embodiments of the invention, the target is a cyst.

[0079] According to some embodiments of the invention, the bodily organ is selected from: a pancreas, a kidney, a liver, and an ovary.

[0080] According to an aspect of some embodiments of the present invention there is provided a method of selective insonation of a cyst, the method comprising: producing first ultrasound waves to selectively image the cyst; and producing second ultrasound waves selectively directed at the cyst, wherein the second ultrasound waves assist in the exfoliation of cells and / or fragments of the cyst.

[0081] According to some embodiments of the invention, the producing second ultrasound waves includes producing ultrasound pulses in a range of from 20-800 us.

[0082] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing a plurality of higher intensity, focused ultrasound beams at the cyst; and directing at least one lower intensity, non-focused ultrasound beam at the cyst.

[0083] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing at the cyst a plurality of higher intensity, focused ultrasound beams, having a Mechanical Index in a range of from 0.4- 1.9; and directing at the cyst at least one lower intensity, non-focused ultrasound beam having a Mechanical Index of less than 0.4.

[0084] According to some embodiments of the invention, the producing the second ultrasound waves includes at least one of: directing at the cyst a plurality of higher intensity, focused ultrasound beams, having a duration in a range of from 1-15 minutes; and directing at the cyst at least one lower intensity, non-focused ultrasound beam having a duration in a range of from 3-30 minutes. According to some embodiments of the invention, the second ultrasound waves cause at least one of: the breaking of cells and / or connections between cells of the epithelium of the cyst; and exfoliation of cells and / or fragments of the cyst.

[0085] According to some embodiments of the invention, the method includes inserting an ultrasound probe into a body and selectively insonating the cyst from inside the body.

[0086] According to some embodiments of the invention, the method further comprises delivering a contrast agent to the cyst.

[0087] According to some embodiments of the invention, the contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

[0088] According to some embodiments of the invention, the producing the second ultrasound waves includes directing at least one lower intensity, non-focused ultrasound beam at the cyst, concurrently with or before the delivering a contrast agent.

[0089] According to some embodiments of the invention, the delivering a contrast agent is performed by one of: delivering the contrast agent intravenously; and delivering contrast agent directly into the cyst.

[0090] According to some embodiments of the invention, the cyst is a pancreatic cyst, and wherein the method includes collecting a sample from one of: the cyst, a pancreatic duct, and a duodenum.

[0091] According to some embodiments of the invention, the method includes collecting a sample of at least one of fluid and cells originating from the cyst.

[0092] According to some embodiments of the invention, the method includes inserting at least one needle to collect a sample originating from the cyst.

[0093] According to some embodiments of the invention, the at least one needle is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

[0094] According to some embodiments of the invention, the collecting includes collecting the sample from a pancreatic ampulla.

[0095] According to some embodiments of the invention, the collecting includes collecting the sample with a suction channel of an endoscope.

[0096] According to some embodiments of the invention, the cyst is a pancreatic cyst, and wherein the collecting includes administering secretin or a secretin bioequivalent to induce secretion of pancreatic juice. According to some embodiments of the invention, the collecting includes collecting pancreatic juice using a suction channel of an endoscope advanced into a duodenum adjacent a pancreatic ampulla.

[0097] According to some embodiments of the invention, the collecting includes collecting at least one of fluid, cells, and fragments originating from the cyst.

[0098] According to some embodiments of the invention, the cyst is in or adjacent to a bodily organ selected from: a pancreas, a kidney, a liver, and an ovary.

[0099] According to an aspect of some embodiments, a cell collection device comprises: an endoscope comprising a probe configured to: produce ultrasound waves configured to image a bodily organ; produce ultrasound waves to form a wide beam; produce ultrasound waves to form focused beams; produce ultrasound pulses of e.g. 20us or up to 800us; and a needle deployable to perform a fine needle aspiration.

[0100] According to an aspect of some embodiments, a method of sampling a pancreatic cyst comprise: inserting an endoscope tube into a stomach region, the endoscope tube comprising an ultrasound probe on a terminal region thereof; directing at a pancreas ultrasound waves configured to image the pancreas; detecting a pancreatic cyst within a volume of the pancreas; directing the ultrasound probe to the pancreatic cysts; generating ultrasound waves in a manner configured to cause exfoliation of epithelial cells of the pancreatic cyst; inserting a needle into the pancreatic cyst; and collecting fluid from the pancreatic cysts with the needle.

[0101] According to some embodiments, the method further comprises delivering contrast agent intravenously.

[0102] According to some embodiments, the method further comprises delivering contrast agent into the pancreatic cyst.

[0103] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0104] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0105] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0106] The drawings and the description herein are not intended to limit the scope of the invention. It should be understood by persons skilled in the art that certain features described herein may be omitted, additional features may be included, and / or features described herein may be combined in a manner different from the specific combinations recited herein, all without departing from the spirit of the invention.

[0107] In the drawings:

[0108] FIG. 1 is a schematic view of an endoscopic ultrasound system in position for visualizing a pancreas, in accordance with an embodiment of the invention;

[0109] FIG. 2 is a schematic view of the endoscopic ultrasound system of Fig. 1 with a probe directed at a cyst located within the pancreas, in accordance with an embodiment of the invention;

[0110] FIG. 3 is a schematic view of the endoscopic ultrasound system of Fig. 1, with a probe directing focused ultrasound beams to a cyst located within the pancreas, in accordance with an embodiment of the invention;

[0111] FIG. 4 is a schematic view of the endoscopic ultrasound system of Fig. 1 with a probe directing at least one non-focused ultrasound beam to a cyst located within the pancreas, in accordance with an embodiment of the invention;

[0112] FIG. 5 is a schematic view of the endoscopic ultrasound system of Fig. 1 with a needle deployed into a cyst located within the pancreas, in accordance with an embodiment of the invention;

[0113] FIG. 6 is a schematic representation of a system for imaging, exfoliation of cells, and collections of exfoliated cells of a pancreas, according to some embodiments;

[0114] FIG. 7 is a flowchart illustrating a method performed by a system for imaging, exfoliation of cells, and collection of exfoliated cells of a pancreas, according to some embodiments;

[0115] FIG. 8 is a flowchart illustrating a method of performing identification of a pancreatic cyst, inducing exfoliation of cystic cells and tissue fragments, and collecting cystic fluid, using the endoscopic ultrasound system of Fig. 1, according to some embodiments; and FIG. 9 is a flowchart illustrating a method of using the endoscopic ultrasound system of Fig. 1, according to some embodiments.

[0116] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0117] The present invention, in some embodiments thereof, relates to the field of medical diagnostics and, more particularly, but not exclusively, to an apparatus and method for imaging a target such as, for example, a cyst located within a bodily organ such as, for example, a pancreas, a kidney, a liver, or an ovary, and directing ultrasound waves (also referred to herein as “beams”) to the target, inducing exfoliation of cyst cells for collection, and optionally collection of the exfoliated cyst cells. While the discussion herein may relate to insonating a target such as, for example, a pancreatic cyst, and colleting a sample originating therefrom, it is to be understood that the invention may relate to insonation of any bodily target and collection of a sample originating therefrom, according to some embodiments.

[0118] Overview

[0119] An aspect of some embodiments relates to an apparatus, system, and method for selectively insonating a target such as, for example, a pancreatic cyst located within a pancreas, a liver, a kidney, or an ovary, to image the target and to assist in exfoliating and / or induce exfoliation of cells and / or tissue fragments in the target, according to some embodiments. Optionally, a sample of material originating in the target is also collected for analysis / diagnosis, according to some embodiments.

[0120] The selectively insonating incudes imaging the target and directing ultrasound waves and / or shear waves configured to break up epithelium lining a cyst and cause such cells to at least partially separate from the cyst wall, thereby exfoliating into the cyst fluid, according to some embodiments. In embodiments of the invention, a probe provided on an endoscope is configured both to optionally image the target and is configured to produce ultrasound waves that are designed to break up IPMN tissue and cause exfoliation of IPMN cells and tissue / tissue fragments into the cyst fluid, the ultrasound waves emanating from the probe optionally located within the body or, alternatively, the probe located outside the body A potential advantage of selectively insonating the target from a probe located within the body to both image and cause exfoliation is that this prevents damage to other tissues, according to some embodiments. A potential advantage of selectively insonating the target from a probe located outside the body to both image and cause exfoliation is that collection of a sample originating from the target, for example, by a catheter, may be easier and / or simpler to perform, according to some embodiments. It will be understood that, whereas systems and method previously developed by Applicant relate to the non-targeted testing cells of an entire pancreas, the system and methods of embodiments of the invention described herein relate to detecting a feature of interest (e.g. a target cyst) located, for example, within the volume of a pancreas, causing localized exfoliation of cells associated with the feature of interest, and facilitating the collecting of such cells for diagnostic testing.

[0121] According to some embodiments, a sample of the exfoliated cells and / or fragments and or fluid from the target is collected for analysis. Collection of the sample may be performed by any suitable system or method, according to some embodiments. For example, collection may be performed by FNA (fine needle aspiration) which collects fluid from the target, since exfoliated cells / tissue fragments may be present in fluid from the target, according to some embodiments. While FNA may allow removal of fluid and material from the volume of the target, it may, in the same procedure, allow the sampling of material from a wall of the target such as, for example, a cyst wall, according to some embodiments. FNA may allow collection of material from the target, from a pancreatic ampulla, adjacent a duodenum, according to some embodiments. Optionally, collection of the sample may be performed from outside the body, for example, when collecting a sample originating from a target in or near a kidney, according to some embodiments.

[0122] It is noted that insonation of the target may be performed using an ultrasound probe on an endoscope and FNA may be performed using a needle on the endoscope, according to some embodiments. In addition to FNA or as an alternate thereto, a sample originating from the target may be collected by advancing the endoscope into the duodenum, for collecting a sample originating at a pancreatic cyst, the collection optionally performed using the same needle as that used for the FNA, according to some embodiments.

[0123] FNA is, however, one example of collection of material from the target, according to some embodiments. A potential advantage of FNA is that it uses a relatively narrow needle, thereby potentially preventing damage to bodily structures such as, for example, a pancreatic wall, according to some embodiments. Alternatively or additionally to collecting fluid from the target by FNA, collection of a sample from a wall of the target such as, from example, a cyst wall, may be performed by FNB (fine needle biopsy), according to some embodiments.

[0124] An aspect of some embodiments relates to ultrasound methods for insolating a target, which may include at least one of imaging the target and inducing exfoliation of target cells and / or target molecules of IPMNs and collecting a sample of material originating at the target, and to ultrasound and collection devices and systems constructed and / or programmed to use such methods, and to programming ultrasound devices to use such methods. Embodiments of the invention provide an endoscope having an ultrasound probe configured for, both, imaging and for delivery of ultrasound energy configured to induce exfoliation of cyst cells. In use, a physician initially visualizes the target, for example, in a pancreas, and identifies a cyst, according to some embodiments. Once a cyst is located, the physician applies ultrasound energy that is configured to target the cyst (hereinafter, also referred to as “target”) and deliver ultrasound waves of sufficient energy to dislodge cystic cells, according to some embodiments. After application of the exfoliative ultrasound, the physician collects cystic fluid from the IPMN, optionally using a fine needle aspiration technique, according to some embodiments. In embodiments, the cystic fluid contains a higher concentration of cystic cells that were dislodged with ultrasound-induced exfoliation.

[0125] Without being bound by theory, it is believed that higher intensity, focused ultrasound insonation, in a first period, for example, as discussed herein, loosens up material from the epithelial layer of a target such as, for example, a pancreatic cyst, according to some embodiments. It is also believed that lower intensity, non-focused ultrasound insonation in a second period, for example, as discussed herein, causes exfoliation of material that was loosened up during the first period of insonation, according to some embodiments.

[0126] A broad aspect of some embodiments of the invention includes insonating an IPMN with higher intensities of focused ultrasound waves during the first period of time, according to some embodiments. The higher intensity focused ultrasound waves may have a Mechanical Index in range of, for example, from 0.4 to 1.9, such as, for example, from 0.4-.9, from 0.9- 1.4, or from 1.4- 1.9, according to some embodiments, It is noted, however, that the Mechanical Index may be higher or lower such as, for example, discussed in any of Applicant’s other patent applications, according to some embodiments.

[0127] The higher intensity, focused ultrasound waves generate shear waves directed at the target, according to some embodiments. In embodiments of the invention, the shear waves are configured to partially segment the target epithelium by breaking cells or connections between cells in order to induce exfoliation of cells and tissue fragments.

[0128] Embodiments of the invention further include insonating the IPMN with lower intensity nonfocused ultrasound (LINFU) waves during the second period of time. The lower intensity focused ultrasound waves may have a Mechanical Index of, for example, less than 0.4 such as, for example. 0.1, 0.2, or 0.3, according to some embodiments. It is noted, however, that the Mechanical Index may be higher or lower such as, for example, discussed in any of Applicant’s other patent applications, according to some embodiments. The lower intensity, non-focused ultrasonic waves are directed at the cyst to at least partially separate segmented epithelium of the cyst from a wall of the target, in order to induce exfoliation of cells and tissue fragments from the target, according to some embodiments.

[0129] It is noted that the higher intensity insonation of the target may be at least twice as high as the lower intensity insonation, according to some embodiments. For example, the higher intensity insonation may be in a range of from 2-20 times as high as the lower intensity insonation, such as, for example, from 2-5 times as high, form 5-8 times as high, from 8-11 times as high, from 11-14 times as high, from 14-17 times as high, or from 17-20 times as high, according to some embodiments.

[0130] In embodiments, the application of the lower intensity ultrasound waves is used in combination with contrast agent infusion (e.g. microbubbles, nanobubbles or nanodroplets), according to some embodiments. The administration of a contrast agent may be performed concurrently with or after application of the lower intensity ultrasound waves, according to some embodiments. The contrast agent may be administered either through IV or directly into the cyst, optionally through the needle used for collection of fluid and cells, according to some embodiments. The contrast agent is configured to further at least partially separate segmented epithelium from a wall of the target, in order to induce exfoliation of cells and tissue fragments, according to some embodiments.

[0131] It is noted that, in some embodiments, only higher intensity, focused ultrasound is used to insonate the target. In embodiments, only lower intensity, non-focused ultrasound is used to insonate the target, optionally in combination with a contrast agent, for example, as discussed herein, according to some embodiments. In embodiments, both higher intensity, focused ultrasound and lower intensity, non-focused ultrasound are used to insonate the target, the lower intensity, nonfocused ultrasound optionally applied in combination with the administration of a contrast agent, according to some embodiments. Any ultrasound application or combination of ultrasound applications that is configured to induce exfoliation of cystic cells may be referred to as “exfoliative ultrasound” or an “exfoliative routine” herein, according to some embodiments.

[0132] In embodiments of the invention, cystic fluid may be collected using a needle, for example, using an FNA (fine needle aspiration) or FNB (fine needle biopsy) technique, according to some embodiments. In addition to or as an alternative to drawing cystic fluid using a needle or drawing cystic fluid directly by the endoscope, a physician may administer secretin (or a bioequivalent) to induce secretion of pancreatic juice, after which the sample may be collected, according to some embodiments. Preferably, the secretin may be administered after the application of the higher intensity, focused ultrasound waves, according to some embodiments. Optionally, the secretin may be administered during or concurrently with application of the lower intensity, non-focused ultrasound waves, according to some embodiments. In this regard, IPMN’s communicate with the pancreatic ductal system such that pancreatic juice collected at the ampulla will contain cystic cells, the pancreatic juice optionally collected at the ampulla by a suction channel of the endoscope, according to some embodiments.

[0133] It will be understood that in the event that more than a single cyst is located in a pancreas, it would be preferrable to collect fluid using fine needle aspiration techniques subsequent to exfoliative ultrasound from all viewed cysts, in order to associate resultant pathology with particular IPMNs.

[0134] It will be understood that embodiments of the invention provide a method, apparatus and system for inducing exfoliation of a targeted area within an organ for analysis. In embodiments, a targeted area is a pancreatic cyst, which may be understood to be any of various cysts, such as but not limited to IPMNs, Mucinous cystic neoplasms (MCN), Serous cystadenomas (SCA), and Pseudocysts.

[0135] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and / or methods set forth in the following description and / or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0136] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0137] Pancreatic cysts are lined with an epithelium. These epithelial cells are in most cases the ones that become neoplastic, and then cancerous. Embodiments of the invention provide an apparatus and method for increasing exfoliation of such cells for collection and analysis.

[0138] Embodiments of the invention include an endoscope such as an echoendoscope having a probe configured with imaging capabilities, but that also is configured to produce ultrasound waves designed to induce tissue exfoliation, according to some embodiments. Such a system may be referred to herein as a LINFU-EUS (lower intensity non-focused ultrasound-endoscopic ultrasound) device.

[0139] The LINFU-EUS system, device, and method is designed to visualize abnormality in a first configuration and designed to cause exfoliation of a defined anatomic area, in particular a pancreatic cyst, in a second configuration, according to some embodiments.

[0140] In embodiments, the LINFU-EUS device includes an endoscopic ultrasound system, using an echoendoscope (also referred to herein as “endoscope”) which has been modified such that- a high frequency ultrasound array exists at the tip of the endoscope (with or without additional instruments or capabilities, such as a fiber-optic imaging system, a guided needle for performing biopsies, etc.). Such EUS systems use frequencies in a range of from 6MHz to 12Mhz, such as, for example, from 6-8MHz, from 8-10MHz, or from 10-12MHz, according to some embodiments. Such EUS systems have an axial resolution in a range of approximately from 0.1 -0.4mm, such as, for example, from 0.1- 0.2 mm, from 0.2mm-0.3mm, or from 0.3mm to 0.4m, according to some embodiments. Known EUS systems, being ultrasound imaging systems, transmit very short ultrasound pulses (l-2us in length), at high pulse rate, focused and shifted to different lateral orientations, so as to generate a 2D image.

[0141] The LINFU-EUS device in accordance with embodiments of the invention includes regular imaging capabilities, but also is provided with a probe having fundamentally different capabilities — the ability to transmit ultrasound energy sufficient to cause exfoliation of cells, according to some embodiments. For example, the LINFU-EUS device is configured to produce ultrasound at pulse lengths in a range of from 20-800us, such as, for example, from 20-100us, from 100-200us, from 200-300us, from 300-400us, from 400-500us, from 500-600us, from 600-700us, and from 700-800us, according to some embodiments.

[0142] In embodiments of the invention, the LINFU-EUS device is configured to produce at least one ‘wide beam,’ in one mode, for example, by employing many or all elements of the probe, with zero (or very small) delay among them, so as to produce at least one homogeneous, or nearly homogeneous non-focused beam, targeted at, and covering the visualized area, e.g. a pancreatic cyst, according to some embodiments.

[0143] The at least one “wide beam” may be employed concurrently with or shortly after infusion of an ultrasound contrast agent, according to some embodiments. The ultrasound contrast agent may be any suitable contrast agent such as, for example, microbubbles, nanobubbles or nanodroplets, for example, either infused continuously during the time of insonation, or infused in boluses (e.g. every 5 minutes) during the time of insonation, according to some embodiments. Preferably, the ultrasound intensity is kept low, e.g. MK0.3, in order to avoid bubble cavitation (implosion), according to some embodiments. The pulses are in a range of 20-800us in length, according to some embodiments. The pulses are repeated, for example, in a range of from 5 to 30 pulses per second, such as, for example, from 5-10 pulses per second, from 10-15 pulses per second, from 15-20 pulses per second, from 20- 25 pulses per second, or from 25-30 pulses per second, according to some embodiments. The duration of insonation is in a range of from 5-20 minutes such as, for example, from 5-10 minutes, from 10- 15 minutes, or from 15-20 minutes, according to some embodiments.

[0144] In embodiments of the invention, one mode of operation includes at least one ‘wide beam,’ as stated above, and this mode of operation may also be employed together with infusion of an ultrasound contrast agent (e.g. microbubbles, nanobubbles or nanodroplets), according to some embodiments. The ultrasound contrast agent may be either infused continuously during the time of insonation (e.g.5-20 minutes), or infused in boluses, e.g. every 5 minutes during the time of insonation (e.g. 5-20 minutes), according to some embodiments. Alternatively the ultrasound contrast agent may be infused shortly before or after the at least one wide beam insonation, according to some embodiments. The ultrasound contrast agent is injected directly into the cyst, for example, through the needle later employed to collect the liquid - with the exfoliated cells, according to some embodiments. Usually, the ultrasound intensity is kept low, e.g. MK0.3, in order to avoid bubble cavitation (implosion), according to some embodiments.

[0145] In embodiments of the invention, the LINFU-EUS device is configured to produce ‘focused beams,’ e.g. similar to ‘shear waves,’ where several or all elements are used to create a focused beam of higher intensities, e.g. MI=1.4, targeted at the visualized area, e.g. a pancreatic cyst. Then, the focused beam is aimed at different locations within the targeted visualized area, e.g. a pancreatic cyst, according to some embodiments. In embodiments of the invention, these pulses are in a range of from 20us to 800us in length, according to some embodiments The pulses are repeated between 5 to 30 pulses per second, such as, for example, 5-10 pulses per second, 10-15 pulses per second, 15-20 pulses per second, 20-25 pulses per second, or 25-30 pulses per second, according to some embodiments. The pulses are repeated for a period of, e.g. 1-20 minutes, such as, for example, from 1-5 minutes, from 5-10 minutes, from 10-15 minutes, or from 15-20 minutes, according to some embodiments.

[0146] The device is also configured to produce at least one ‘non-focused beams,’ of lower intensity, e.g. MI=less than 0.4, for example, as discuss herein, according to some embodiments. The lower intensity insonation is targeted at the visualized area, according to some embodiments. In embodiments of the invention, these are repeated for a period of, e.g. 3-30 minutes, such as, for example, from 3-6 minutes, from 6-9 minutes, from 9-12 minutes, from 12-15 minutes, from 15-18 minutes, from 18-21 minutes. From 21-24 minutes, from 24-27 minutes, or from 27-30 minutes, according to some embodiments.

[0147] Once the insonation protocols are performed, a sample of material originating in the target is collected, according to some embodiments. Collection may be performed using a needle (part of the endoscope) deployed and directed, for example, toward the targeted organ / organelle, e.g. a pancreatic cyst, and advanced, for example, to penetrate that targeted organ / organelle, and the needle used to collect a sample or samples of the organ / organelle contents (e.g. cystic fluid and / or material), which includes cells that have been exfoliated due the LINFU-EUS process, according to some embodiments. In embodiments of the invention, a contrast agent (e.g. microbubbles, nanobubbles or nanodroplets) may delivered directly into the cyst, in addition to or as an alternative to infusion into the patient’s bloodstream. In this regard, it will be understood that because the process of identifying the cyst includes using an EUS to obtain a biopsy of the cyst contents, it will be possible to inject an amount of contrast material directly into the cyst, according to some embodiments. After delivering contrast agent into the cyst, the needle is withdrawn and an exfoliative ultrasound routine is run, according to some embodiments. Optionally, the contrast agent is delivered into the cyst concurrently with the at least one wide-beam ultrasound routine, according to some embodiments. Once the ultrasound routine is completed, the needle is reintroduced into the cyst to collect cystic fluid, to obtain pancreatic cells and tissue that have been exfoliated into cystic fluid, according to some embodiments.

[0148] The collected sample or samples (specimens) of the organ / organelle contents, with cells that have been exfoliated due the LINFU-EUS process, are preserved and analyzed, so as to detect and identify neoplastic and / or cancerous cells, according to some embodiments. This process may be performed manually or automatically, e.g. by using a Al system, according to some embodiments.

[0149] Embodiments of the invention provide a method for detecting an area or feature of interest (e.g. a cyst or mass) within the volume of an organ (e.g. a pancreas, kidney, liver, ovary etc.), directing exfoliative ultrasound to the area or feature of interest sufficient to induce exfoliation of cells associated with area or feature of interest and collecting such exfoliated cells for diagnostic analysis, according to some embodiments.

[0150] Embodiments of the invention provide a method of collecting cells from pancreatic cysts and includes a method of increasing the yield of epithelial cells in such sample, according to some embodiments.

[0151] With reference of FIG. 1, there is device 50 employed for identifying a cyst such as, for example, a pancreatic cyst 22, inducing exfoliation of cystic cells, and collecting cystic fluid, according to some embodiments.

[0152] Device 50 includes a tube 10 of an LINFU-EUS device, shown threaded down an esophagus 12 and into the stomach 14 of a patient, according to some embodiments. The distal end 16 of tube 10 is provided with one or more probes 18 (hereinafter referred to as “probe 18”), according to some embodiments. As shown, the probe 18 is positioned substantially adjacent to the pancreas 20, according to some embodiments. Optionally, probe 18 includes a phased transducer array for directing ultrasonic waves toward a target such as, for example, a cyst 22, according to some embodiments. Optionally, some of the ultrasonic elements of the phased transducer array may be turned off, if desired, to avoid directing ultrasonic waves toward other, nearby tissues and / or structures, according to some embodiments. This may potentially prevent damage to nearby tissues and / or structures, according to some embodiments.

[0153] The method includes visually scanning the pancreas 20 to detect a presence of a cyst, according to some embodiments.

[0154] In the event that a cyst (e.g. 22) is observed (e.g. via manual visual inspection), the probe is positioned to direct ultrasound energy directly to the cyst, according to some embodiments. FIG. 2 shows a schematic example of a probe positioned to target observed cyst 22, according to some embodiments.

[0155] With reference to FIG. 3, the method further includes configuring the EUS-LINFU device to run an exfoliative routine, according to some embodiments. For example, as shown, in a first phase, focused beams 24 are directed at the cyst 22 (e.g., as shown in Fig. 3), and thereafter at least one nonfocused, wide beam 26 is directed to the cyst 22 (e.g., as shown in FIG. 4), according to some embodiments.

[0156] In embodiments of the invention the method includes optionally introducing a contrast agent such as, for example, microbubbles, nanobubbles or nanodroplets either, intravenously, directly into the cyst or a combination of the two, according to some embodiments, as described in more detail herein.

[0157] With reference to FIG. 5, once the exfoliative routine (and, optionally, application of a contrast agent) is completed, the method further includes collecting a sample of material originating from the target such as, for example, deploying a needle 28 into the lumen of the cyst 22 to collect fluid, which has been enriched to contain an increased number of cyst epithelial cells, according to some embodiments. The sample is then analyzed to detect any cells having features consistent with dysplasia or cancer, according to some embodiments.

[0158] In addition to or as an alternative to drawing cystic fluid using needle 28, a physician may administer secretin (or a bioequivalent) to induce secretion of pancreatic juice. Preferably, the secretin may be administered after the application of the higher intensity, focused ultrasound waves, according to some embodiments. Optionally, the secretin may be administered during or concurrently with application of the lower intensity, non-focused ultrasound waves, according to some embodiments. Since IPMN’s communicate with the pancreatic ductal system, pancreatic juice collected at the ampulla will contain cystic cells, according to some embodiments. The collected sample is then analyzed to detect any cells having features consistent with dysplasia or cancer, according to some embodiments.

[0159] Optionally, instead of positioning the probe 18 in the stomach 14, for example, as shown in Fig. 1, the endoscope tube 10 may be advanced further distally, such that probe 18 is positioned in the duodenum, according to some embodiments. Optionally, the endoscope tube may be advanced yet further distally, such that probe 18 is positioned in the pancreatic duct, according to some embodiments. Optionally, if the probe 18 is positioned in the pancreatic duct, cells / tissue fragments and / or cystic fluid may be collected directly by the endoscope, according to some embodiments.

[0160] FIG. 6 is a schematic representation of a system 60 for imaging, exfoliation of cells, and collections of exfoliated cells of a pancreas, according to some embodiments. System 60 includes endoscopic tube 10 having at least one probe 18 and a needle 28 at a distal portion thereof (for example, as shown in Fig. 5), according to some embodiments. System 60 also includes a memory 62, circuitry 64, and a user interface 66, according to some embodiments. The circuitry 64 is located proximal to the probe 18 such that circuitry 64 is positioned outside the body, according to some embodiments.

[0161] The user interface 66 may include controls for operating the endoscope, including advancing / retracting and directing the endoscopic tube 10 toward a target, according to some embodiments. The user interface 66 may also include an actuator for initiating imaging via the ultrasonic probe 18, according to some embodiments. The user interface 66 may also include an actuator for initiating higher intensity, focused ultrasonic insonation of a target, and / or for initiating lower intensity, non-focused ultrasonic insonation of the target, according to some embodiments. The user interface may include settings for application of ultrasound insonation, for example, as discussed herein, according to some embodiments.

[0162] The user interface 66 may optionally be used to initiate tracking of the target (for example, actions 110 and / or 118 in Fig. 6), according to some embodiments. The user interface may further be used to infuse a contrast agent, such as, for example, discussed herein, into the cyst, according to some embodiments. Yet further, the user interface may be used to induce secretion of pancreatic juice, for example, as discussed herein, according to some embodiments. Yet further, the user interface may be used to direct needle 28 to collect a sample, for example, as discussed herein, according to some embodiments.

[0163] Memory 62 may be used to record, for example, a location of a cyst 22 imaged by probe 18, according to some embodiments. The recorded location of the cyst may be required, for example, for optional tracking of the cyst (for example, actions 110 and 118 in Fig. 7), according to some embodiments.

[0164] Based on input from the user interface 66, circuitry 64 may be used to control imaging (for example, action 102 in Fig. 6) of, for example, cyst 22 via the probe 18, according to some embodiments. Circuitry 64 may also be used to control application of ultrasonic insonation, 24 and 26 (for example, actions 104 and 112 in Fig. 6), via the probe 18, optionally upon instructions received from the user interface 66, according to some embodiments. Further, circuitry 64 may be used to control the administration of contrast material, for example, as discussed herein, according to some embodiments. Circuitry 64 may also be used to control induction of secretion of pancreatic juice (action 120 in Fig. 6), according to some embodiments. Circuitry 64 may further be used to guide movement of needle 28 (for example, action 122 in Fig. 6), including advancing / retracting of needle 28, as well as adjusting an angle of needle 28 such that the needle is directed at the target, or at the duodenum, or at the pancreatic duct, according to some embodiments.

[0165] Optionally, the system 60 may be automatic or semi-automatic, according to some embodiments. For example, tracking of cyst 22 (action 110 and / or 118 in Fig. 7) may optionally be performed automatically, according to some embodiments. Optionally, after performing action 108, and device 50 (Fig. 1, according to some embodiments.

[0166] FIG. 7 is a flowchart illustrating a method 100 performed by a system for imaging, exfoliation of cells, and collection of exfoliated cells in a pancreas, according to some embodiments. It is to be understood that the method may, alternatively, be performed on any other body portion such as, for example, a liver, a kidney, or an ovary, according to some embodiments.

[0167] According to method 100, at 102, the system is in imaging mode, according to some embodiments. The pancreas 20 is imaged to identify the location of a cyst in the pancreas (Fig. 1), according to some embodiments.

[0168] At 104, the system is in higher intensity ultrasound mode, for example, as discussed herein, according to some embodiments. The higher intensity ultrasound waves are focused to generate shear waves which are directed at the cyst 22 (Fig. 3), according to some embodiments. Optionally, the cyst may not be selectively insonated but, rather, the entire pancreas may be insonated, according to some embodiments.

[0169] The shear waves partially segment the target epithelium of the cyst by breaking cells or connections between cells in the cyst, according to some embodiments.

[0170] Optionally, at 110, the target cyst 22 may be tracked, to determine whether or not the target has moved, for example, relative to the probe 18, according to some embodiments. For example, the target may have moved, for example, relative to the probe, if the patient has moved or has been repositioned, according to some embodiments. If it is determined that the target cyst has moved, method 100 may return to action 102 for reimaging to relocate the cyst, according to some embodiments. Action 104 may be repeated, if it is determined that breaks have not been created, or that insufficient breaks have been created, according to some embodiments.

[0171] At 112, the system is in lower intensity ultrasound mode, for example, as discussed herein, according to some embodiments. The lower intensity, non-focused ultrasound waves are directed at the cyst (Fig. 4) to at least partially separate segmented epithelium of the cyst 22 from a wall of the target, according to some embodiments. Optionally, the cyst may not be selectively insonated but, rather, the entire pancreas may be insonated, according to some embodiments. The lower intensity ultrasound insonation induces exfoliation of cells and tissue fragments from the cyst, according to some embodiments.

[0172] Optionally, at 114, a contrast agent is infused into the cyst, according to some embodiments. The contrast agent may be infused into the cyst concurrently with or after action 112, according to some embodiments. The contrast agent may include microbubbles, nanobubbles, or nanodroplets, according to some embodiments . This action may be performed either through IV infusion or direct infusion into the cyst 22, according to some embodiments.

[0173] Additionally, is noted that stable cavitation of the contrast material may facilitate the exfoliation of cells / tissue fragments in the cyst, according to some embodiments. Imaging of the cyst will allow the system to determine whether or not cavitation is stable, according to some embodiments. If cavitation is not observed, actions 112 and / or 114 may be repeated and / or action 106 may be repeated, and / or the intensity of ultrasound insonation applied at action 112 may be increased, according to some embodiments. If cavitation is observed as being inertial, the intensity of ultrasound insonation applied at action 112 may be reduced, according to some embodiments.

[0174] Optionally, at 118, the target cyst 22 may be tracked, to determine whether or not the target has moved, for example, relative to the probe 18, according to some embodiments. For example, the target may have moved, for example, relative to the probe, if the patient has moved or has been repositioned, according to some embodiments. If it is determined that the target cyst has moved, method 100 may return to action 102 for reimaging to relocate the cyst, according to some embodiments. Action 112 may be repeated, if it is determined that exfoliation of cells and tissue fragments has not been induced or is insufficient, according to some embodiments.

[0175] It should be noted that, optionally, it may be decided to insonate the cyst / pancreas with lower intensity, non-focused ultrasound insonation only and, consequently, actions 104 and 110 may not be performed, according to some embodiments. It should be noted further that, optionally, it may be decided to insonate the cyst / pancreas with higher intensity, focused ultrasound beams only and, consequently, actions 112, 114, and 118 may not be performed, according to some embodiments.

[0176] Optionally, at 120, secretion of pancreatic juice is induced, according to some embodiments. This may be accomplished by administration of secretin or a bioequivalent, to induce secretion of pancreatic juice, according to some embodiments. It is noted that, preferably, the secretin is administered after the application of the higher intensity, focused ultrasound waves (action 104), according to some embodiments. Optionally, the secretin may be administered during or concurrently with application of the lower intensity, non-focused ultrasound waves (action 112), according to some embodiments.

[0177] At 122, the system is in sampling mode, wherein needle is guided to collect cystic fluid and / or cells and / or tissue fragments, according to some embodiments. Collection of cells / tissue fragments and / or collection of cystic fluid may be performed at the cyst, in the pancreatic duct, or in the duodenum, for example, as discussed herein, according to some embodiments. Collection of cells / tissue fragments may be performed by an FNA technique or by an FNB, according to some embodiments. The pancreatic fluid and / or cells / tissue fragments / cystic fluid may be collected from the pancreatic duct (action 122), , optionally using a suction channel of the endoscope, according to some embodiments.

[0178] Optionally, the location the cyst 22 in the image, which was determined in action 102, may be recorded in memory 62 (Fig. 6), according to some embodiments. The system 60 may automatically advance from action 104 to action 112, optionally repeating either of actions 104 and 112, according to some embodiments.

[0179] With reference to FIG. 8 there is shown is a flowchart illustrating a method 200 of performing identification of a pancreatic cyst, inducing exfoliation of cystic cells and tissue fragments, and collecting cystic fluid, using the endoscopic ultrasound system 60 (Fig. 6), according to some embodiments.

[0180] According to method 200, at 202, the location of a cyst in the pancreas 20 (Fig. 1) is identified, according to some embodiments. The cyst is identified by visually scanning the pancreas 20, according to some embodiments.

[0181] At 204, shear waves are generated by higher intensity focused ultrasound beams 24 (Fig. 3) which are directed at the cyst 22, according to some embodiments. The shear waves partially segment the target epithelium of the cyst by breaking cells or connections between cells in order to induce exfoliation of cells and tissue fragments in the cyst, according to some embodiments.

[0182] At 206, segmented epithelium of the cyst 22 is at least partially separated from the wall of the target, to induce exfoliation of cells and tissue fragments from the cyst, according to some embodiments. This is accomplished by directing lower intensity non-focused ultrasound (LINFU) waves at the cyst 22 (Fig. 4), according to some embodiments.

[0183] Optionally, at 208, a contrast agent is infused into the cyst, according to some embodiments. The contrast agent may be infused into the patient’s blood stream or into the cyst, concurrently with or after action 206, according to some embodiments. The contrast agent may include microbubbles, nanobubbles, or nanodroplets, according to some embodiments . This action may be performed either through IV infusion or direct infusion into the cyst 22, according to some embodiments. Optionally, at 210, secretion of pancreatic juice is induced, according to some embodiments. This may be accomplished by administration of secretin or a bioequivalent, to induce secretion of pancreatic juice, according to some embodiments. It is noted that, preferably, the secretin is administered after the application of the higher intensity, focused ultrasound waves (action 204), according to some embodiments. Optionally, the secretin may be administered during or concurrently with application of the lower intensity, non-focused ultrasound waves (action 206), according to some embodiments.

[0184] Cystic fluid and / or cells are collected, at 212, according to some embodiments. Collection of cells / tissue fragments and / or collection of cystic fluid may be performed at the cyst, in the pancreatic duct, or in the duodenum, according to some embodiments. Collection of cells / tissue fragments may be optionally performed by an FNA or FNB technique, or by a suction channel of the endoscope, according to some embodiments.

[0185] FIG. 9 is a flowchart illustrating a method 300 of using the endoscopic ultrasound system of Fig. 1, according to some embodiments.

[0186] According to method 300, at 302, the pancreas 20 is visualized to identify the location of a cyst in the pancreas (Fig. 1), according to some embodiments. The cyst is identified by visually scanning the pancreas 20, according to some embodiments.

[0187] At 304, higher intensities of focused ultrasound beams 24 (Fig. 3) are directed at the cyst 20, according to some embodiments. This generates shear waves to partially segment the target epithelium of the cyst by breaking cells or connections between cells in order to induce exfoliation of cells and tissue fragments in the cyst, according to some embodiments.

[0188] At 306, at least one lower intensity non-focused ultrasound (LINFU) beam is applied to the cyst 22 (Fig. 4), according to some embodiments. This causes segmented epithelium of the cyst 22 to be at least partially separated from a wall of the target, to induce exfoliation of cells and tissue fragments from the target / cyst, according to some embodiments.

[0189] Optionally, at 308, a contrast agent is infused into the cyst, according to some embodiments. This may be performed concurrently with or after action 306, according to some embodiments. The contrast agent may include microbubbles, nanobubbles, or nanodroplets, according to some embodiments. This action may be performed either through IV infusion or direct infusion into the cyst 22, according to some embodiments.

[0190] Optionally, at 310, secretion of pancreatic juice is induced, according to some embodiments. This may be accomplished by administration of secretin or a bioequivalent, to induce secretion of pancreatic juice, according to some embodiments. Preferably, the secretin is administered after the application of the higher intensity, focused ultrasound waves (action 304), according to some embodiments. Optionally, the secretin may be administered during or concurrently with application of the lower intensity, non-focused ultrasound waves (action 306), according to some embodiments.

[0191] Cystic fluid and / or cells are collected, at 312, according to some embodiments, collection of cells / tissue fragments and / or collection of cystic fluid may be performed, at the cyst, in the pancreatic duct, or in the duodenum, according to some embodiments, collection of cells / tissue fragments may be performed by an FNA or FNB technique, or via a suction channel of the endoscope, according to some embodiments.

[0192] After collection of a sample originating from the target, the sample is analyzed, for example, by examining collected cells and / or sheets of cells, and analysis of the collected sample allows diagnosis of the target from which the sample was collected, to determine whether or not the target is malignant, according to some embodiments.

[0193] In the event of a diagnosis of cancer, appropriate treatment is considered such as, for example, at least one of surgical removal of the cyst and / or part of the bodily organ in which the cyst is attached, ablation of the cyst, chemotherapy, and radiation therapy.

[0194] While this invention has been described in conjunction with the embodiments outlined above, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, the exemplary embodiments of the invention, as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention.

[0195] It is expected that during the life of a patent maturing from this application many relevant ultrasound devices will be developed and the scope of the term ultrasound is intended to include all such new technologies a priori.

[0196] As used herein the term “about” refers to ± 10 %.

[0197] The terms "comprises,” "comprising,” "includes,” "including,” “having” and their conjugates mean "including but not limited to.”

[0198] The term “consisting of’ means “including and limited to.”

[0199] The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0200] As used herein, the singular form "a,” "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof. Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0201] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0202] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0203] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0204] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0205] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. It is the intent of the Applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is / are hereby incorporated herein by reference in its / their entirety.

Claims

WHAT IS CLAIMED IS:

1. A cell collection system comprising an endoscope including: a probe configured to produce first ultrasound waves configured to: image a target, wherein said system includes circuitry to control the first ultrasound waves; and selectively insonate a target in a bodily organ to assist in exfoliation of cells and / or fragments of the target, wherein the system includes circuitry to produce second ultrasound waves for said selective insonation.

2. The system according to claim 1, wherein said probe is configured to produce ultrasound pulses in a range of from 20-800 us.

3. The system of claim 1, wherein said probe is configured to be inserted into a body to selectively insonate the target from inside the body.

4. The system of claim 1, wherein said collection device is deployed from said endoscope while said endoscope is positioned inside a body.

5. The system according to claim 1, wherein said second ultrasound waves include at least one of: a plurality of higher intensity ultrasonic beams directed at the target; and at least one lower intensity, non-focused ultrasonic beam directed at the target.

6. The system according to claim 1, wherein said second ultrasound waves include at least one of: a plurality of higher intensity, focused ultrasonic beams directed at the target, wherein said higher intensity, focused ultrasonic beams have a Mechanical Index in a range of approximately 0.4 to 1.9; and at least one lower intensity, non-focused ultrasonic beam directed at the target, wherein said at least one lower intensity ultrasonic beam has a Mechanical Index of less than 0.4.

7. The system according to claim 1, wherein said second ultrasound waves include at least one of: a plurality of higher intensity, focused ultrasonic beams directed at the target, wherein said higher intensity, focused ultrasonic beams have a duration in a range of from 1-15 minutes; and at least one lower intensity, non-focused ultrasonic beam directed at the target, wherein said at least one lower intensity ultrasonic beam has a duration in a range of from 3-30 minutes.

8. The system according to claim 1, wherein said second ultrasound waves are directed at the target to cause at least one of:the creation of breaks between cells and / or connections between cells of the epithelium of the target; and exfoliation of cells and / or fragments of the target.

9. The system according to claim 1, wherein the exfoliation of cells and / or fragments of the target is enhanced by the administration of a contrast agent into the target.

10. The system according to claim 9, wherein said contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

11. The system according to claim 1, wherein the bodily organ is selected from: a pancreas, a kidney, a liver, and an ovary.

12. The system according to claim 1, including a collecting device deployable to collect a sample originating from the target.

13. The system of claim 12, wherein said collecting device is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

14. The system of claim 12, wherein said collecting device is a portion of said endoscope.

15. The system of claim 12, wherein said collecting device is automatically deployable to collect the sample.

16. The system of claim 11, wherein the bodily organ is a pancreas, and wherein said system is configured to automatically administer to the pancreas one of secretin and a bioequivalent of secretin, before deployment of said collecting device.

17. A cell collection system including: an endoscope comprising a probe, wherein said system has at least one insonation mode in which said probe selectively directs ultrasound waves directed at a target in a bodily organ; a memory for recording data obtained by the ultrasound waves, in a recording mode; and a user interface for actuating operation of said probe and said memory; and circuitry for controlling operation of said endoscope and said probe, wherein said circuitry is configured to switch among said at least one insonation mode and said recording mode.

18. The system of claim 17, further including a collection device for collecting a sample originating from the target, in a collecting mode; wherein said user interface is configured for actuating operation of said collection device; and wherein said circuitry is configured for controlling operation of said collection device.

19. The system of claim 18, wherein said collection device is automatically actuated.

20. The system of claim 17, wherein said user interface provides an indication as to which of said at least one insonation mode, said recording mode, and said collection mode is currently operational.

21. The system of claim 17, wherein said collection device is at least one needle.

22. The system of claim 18, wherein said collection device is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

23. The system of claim 18, wherein said collection device is a portion of said endoscope.

24. The system of claim 17, wherein said probe is configured to be inserted into a body to selectively insonate the target from inside the body.

25. The system of claim 17, wherein said user interface provides an indication as to which of said at least one insonation mode and said recording mode is currently operational.

26. The system of claim 17, wherein said at least one insonation mode includes: an imaging mode; and at least one of: a first insonation mode in which said probe directs a plurality of higher intensity, focused ultrasonic beams at the target; and a second insonation mode in which said probe directs at least one non-focused, lower intensity ultrasonic beam at the target.

27. The system of claim 26 wherein said probe is configured to insonate the target in the first insonation mode, wherein the plurality of higher intensity, focused ultrasonic beams have a mechanical index in a range of from 0.4- 1.9.

28. The system of claim 26 wherein said probe is configured to insonate the target in the second insonation mode, wherein the at least one non-focused ultrasonic beam has a Mechanical Index of less than 0.4.

29. The system of claim 26 wherein said probe is configured to insonate the target in the first insonation mode, wherein the plurality of higher intensity, focused ultrasonic beams have a duration in a range of from 1-15 minutes.

30. The system of claim 26, wherein said probe is configured to insonate the target in the second insonation mode, wherein the at least one non-focused ultrasonic beam has a duration in a range of from 3-30 minutes.

31. The system of claim 17, wherein at least one of said probe, said memory, and said collection device is automatically actuated.

32. Medical of use of a contrast material for cell collection from a target in a bodily organ, wherein the contrast material enhances at least one of:the breaking of cells and / or connections between cells of the target epithelium; and the exfoliation of cells and / or fragments of the target.

33. Medical use of a contrast material according to claim 32, wherein said contrast material is used in conjunction with insonation of the target to produce said enhancement.

34. Medical use of a contrast material according to claim 33, wherein said insonation includes at least one of: the direction of a plurality of higher intensity, focused ultrasonic beams at the target; and the direction of at least one wide, non-focused ultrasonic beam at the target.

35. Medical use of a contrast material according to claim 34, wherein said contrast material is administered concurrently with or after the direction of the at least one wide ultrasonic beam at the target.

36. Medical use of a contrast material according to claim 32, wherein said contrast material is configured to induce and / or assist in exfoliation of cystic cells and tissue fragments in the target.

37. Medical use of a contrast material according to claim 36, wherein said contrast material is configured to at least partially separate segmented epithelium of the target from a wall of the target.

38. Medical use of a contrast material according to claim 32, wherein the contrast material is selected from microbubbles, nanobubbles, and nanodroplets.

39. Medical use of a contrast material according to claim 32, wherein the contrast material is one of: infused through IV; and infused directly into the target.

40. Medical use of secretin or a bioequivalent of secretin for cell collection from a target in a pancreas, wherein the secretin is administered after insonation of the target to assist in exfoliation of cells and / or fragments of an epithelium of the target.

41. Medical use of secretin or a bioequivalent of secretin according to claim 40, wherein said insonation includes at least one of: the direction of a plurality of focused, higher intensity ultrasonic beams at the target; and the direction of at least one non-focused, lower intensity ultrasonic beam at the target.

42. Medical use of secretin or a bioequivalent of secretin according to claim 41, wherein the secretin or a bioequivalent of secretin is administered one of: after said direction of the plurality of focused, higher intensity ultrasonic beams at the target; and prior to or concurrently with said the direction of at least one non-focused, lower intensity ultrasonic beam at the target.

43. A method of collecting a sample originating from a target in a bodily organ, said method comprising: insonating the target to assist in exfoliation of epithelial cells of the target; and collecting the sample originating from the target.

44. The method of claim 43, wherein said insonating is selective insonating of the target.

45. The method of claim 43 wherein said insonating includes: producing first ultrasound waves to image the target; and producing second ultrasound waves directed at the target, wherein the second ultrasound waves assist in the exfoliation of cells and / or fragments of the target.

46. The method of claim 45, wherein said producing second ultrasound waves includes producing ultrasound pulses in a range of from 20-800 us.

47. The method of claim 45, wherein said producing the second ultrasound waves includes at least one of: directing a plurality of higher intensity, focused ultrasound beams at the target; and directing at least one lower intensity, non-focused ultrasound beam at the target.

48. The method of claim 45, wherein said producing the second ultrasound waves includes at least one of: directing at the target a plurality of higher intensity, focused ultrasound beams, having a Mechanical Index in a range of from 0.4- 1.9; and directing at the target at least one lower intensity, non-focused ultrasound beam having a Mechanical Index of less than 0.4.

49. The method of claim 45, wherein said producing the second ultrasound waves includes at least one of: directing at the target a plurality of higher intensity, focused ultrasound beams, having a duration in a range of from 1-15 minutes; and directing at the target at least one lower intensity, non-focused ultrasound beam having a duration in a range of from 3-30 minutes.

50. The method of claim 45, wherein the second ultrasound waves cause at least one of: the breaking of cells and / or connections between cells of the epithelium of the target; and exfoliation of cells and / or fragments of the target.

51. The method of claim 43, wherein said insonating the target includes inserting an ultrasound probe into a body and selectively insonating the target from inside the body.

52. The method of Claim 43, further comprising delivering a contrast agent to the target.

53. The method according to claim 52, wherein the contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

54. The method of claim 52, wherein said insonating includes directing at least one lower intensity, non-focused ultrasound beam at the target, concurrently with or before said delivering a contrast agent.

55. The method of Claim 52, wherein said delivering a contrast agent is performed by one of: delivering the contrast agent intravenously; and delivering contrast agent directly into the target.

56. The method of claim 43, wherein the target is a pancreatic cyst, and wherein the sample is collected from one of: the target, a pancreatic duct, and a duodenum.

57. The method of claim 43, wherein said collecting includes collecting a sample of at least one of fluid and cells originating from the target.

58. The method of claim 43, wherein said collecting includes inserting at least one needle to collect the sample.

59. The method of claim 58, wherein the at least one needle is at least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

60. The method of claim 43, wherein said collecting includes collecting the sample from a pancreatic ampulla.

61. The method of claim 60, wherein said collecting includes collecting the sample with a suction channel of an endoscope.

62. The method of claim 43, wherein the target is a pancreatic cyst, and wherein said collecting includes administering secretin or a secretin bioequivalent to induce secretion of pancreatic juice.

63. The method of claim 62, wherein said collecting pancreatic juice includes using a suction channel of an endoscope advanced into a duodenum, adjacent a pancreatic ampulla.

64. The method of claim 43, wherein said collecting a sample includes collecting at least one of fluid, cells, and fragments originating from the target.

65. The method of claim 43, wherein the target is a cyst.

66. The method of claim 43, wherein the bodily organ is selected from: a pancreas, a kidney, a liver, and an ovary.

67. A method of selective insonation of a cyst, said method comprising: producing first ultrasound waves to selectively image the cyst; and producing second ultrasound waves selectively directed at the cyst, wherein the second ultrasound waves assist in the exfoliation of cells and / or fragments of the cyst.

68. The method of claim 67, wherein said producing second ultrasound waves includes producing ultrasound pulses in a range of from 20-800 us.

69. The method of claim 67, wherein said producing the second ultrasound waves includes at least one of: directing a plurality of higher intensity, focused ultrasound beams at the cyst; and directing at least one lower intensity, non-focused ultrasound beam at the cyst.

70. The method of claim 67, wherein said producing the second ultrasound waves includes at least one of: directing at the cyst a plurality of higher intensity, focused ultrasound beams, having a Mechanical Index in a range of from 0.4- 1.9; and directing at the cyst at least one lower intensity, non-focused ultrasound beam having a Mechanical Index of less than 0.4.

71. The method of claim 67, wherein said producing the second ultrasound waves includes at least one of: directing at the cyst a plurality of higher intensity, focused ultrasound beams, having a duration in a range of from 1-15 minutes; and directing at the cyst at least one lower intensity, non-focused ultrasound beam having a duration in a range of from 3-30 minutes.

72. The method of claim 67, wherein the second ultrasound waves cause at least one of: the breaking of cells and / or connections between cells of the epithelium of the cyst; and exfoliation of cells and / or fragments of the cyst.

73. The method of claim 67, wherein said method includes inserting an ultrasound probe into a body and selectively insonating the cyst from inside the body.

74. The method of Claim 67, further comprising delivering a contrast agent to the cyst.

75. The method according to claim 74, wherein the contrast agent includes at least one of microbubbles, nanobubbles, and nanodroplets.

76. The method of claim 74, wherein said producing the second ultrasound waves includes directing at least one lower intensity, non-focused ultrasound beam at the cyst, concurrently with or before said delivering a contrast agent.

77. The method of Claim 52, wherein said delivering a contrast agent is performed by one of: delivering the contrast agent intravenously; and delivering contrast agent directly into the target.

78. The method of claim 67, wherein the cyst is a pancreatic cyst, and wherein said method includes collecting a sample from one of: the cyst, a pancreatic duct, and a duodenum.

79. The method of claim 67, wherein said method includes collecting a sample of at least one of fluid and cells originating from the cyst.

80. The method of claim 43, wherein said method includes inserting at least one needle to collect a sample originating from the target.

81. The method of claim 43, wherein said collecting includes deployingat least one of: a needle for performing FNA (fine needle aspiration); and a needle for performing FNB (fine needle biopsy).

82. The method of claim 79, wherein said collecting includes collecting the sample from a pancreatic ampulla.

83. The method of claim 79, wherein said collecting includes collecting the sample with a suction channel of an endoscope.

84. The method of claim 79, wherein the cyst is a pancreatic cyst, and wherein said collecting includes administering secretin or a secretin bioequivalent to induce secretion of pancreatic juice.

85. The method of claim 79, wherein said collecting includes collecting pancreatic juice using a suction channel of an endoscope advanced into a duodenum adjacent a pancreatic ampulla.

86. The method of claim 79, wherein said collecting includes collecting at least one of fluid, cells, and fragments originating from the cyst.

87. The method of claim 67, wherein the cyst is in or adjacent to a bodily organ selected from: a pancreas, a kidney, a liver, and an ovary.

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