Patent Publication Number: US-2022211953-A1

Title: Fine needle injection therapy device

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application Ser. No. 62/821,717, filed Mar. 21, 2019. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application. 
    
    
     BACKGROUND 
     1. Technical Field 
     This document relates to methods and materials for improving cancer treatment. For example, this document relates to methods and devices for local tumor control and customizable patient treatment. 
     2. Background Information 
     Chemotherapy and radiation therapy have been used to treat pancreatic ductal adenocarcinoma (PDAC). Despite the introduction of many new agents touted to transform care and outcomes, the median survival expectancy for locally advanced pancreatic cancer (LAPC) remains at only 9-11 months, even with the administration of chemoradiotherapy, and only at 6 months for patients with metastatic disease. Neoadjuvant therapy is routinely administered to patients with LAPC with the aim of tumor downstaging to potentially allow subsequent resection. Unfortunately, for patients who have unresectable tumors, excluding borderline resectable status, chemoradiotherapy seldom leads to tumor downstaging and a complete resection with negative margins. Prolonged survival is rare. A great challenge to the delivery of systemic chemotherapy is the suboptimal intratumoral penetration of therapy that occurs secondary to a hostile tumor microenvironment that is partly attributed to tumor-induced stromal desmoplasia. Therefore, despite recent advances, chemoradiation serves only a palliative role in treatment of most patients with PDAC. 
     The limited efficacy of conventional PDAC therapy results from the tumor biology, severe desmoplasia and altered tumor-induced biophysical properties that result in neoplastic islands interspersed among dense stroma. This resulting tumor structure topography alters the pattern and limits chemotherapy penetrance to the tumor. 
     Many of the biological and technical limitations apply to other solid pancreatic tumors (e.g., functioning and non-functioning neuroendocrine tumors, lymphoma, secondary metastasis to the pancreas, etc.). There are also several cystic pancreatic tumors (CPT) such as intraductal papillary mucinous neoplasia, mucinous cystic neoplasia, and serous cystadenomas, among others that experience the biological and technical limitations. 
     SUMMARY 
     This document describes methods and materials for improving the delivery of cancer treatment. For example, this document describes methods and devices for local tumor control and customizable patient treatment. 
     In one aspect, this disclosure is directed to a method of providing treatment to a patient. The method includes delivering a mixture to a targeted area within the patient. The mixture includes a therapeutic agent, a glue, and a radiopaque substance. In some cases, the therapeutic agent is a chemotherapeutic agent. In some cases, the glue is a cyanoacrylate. In some cases, the radiopaque substance is a lipid-based agent. In some cases, the mixture further includes at least one of a nanoparticle, an alcohol, an anesthetic agent, a radioactive material, a vasoconstricting agent, a vasodilating agent, an ultrasound contrast medium, a ultrasound microbubble, an anti-stromal agent, a pathway inhibitor, an immunotherapy agent, a vaccine, or a combination thereof. In some cases, the method also includes providing a needle for delivery of the mixture. In some cases, the needle defines an inner lumen comprising a coating. In some cases, the coating is at least one of an anticoagulant, a lipid-based agent, an acetone, or a nitromethane. In some cases, the method also includes providing a needle for delivery of the mixture. In some cases, the needle includes a first lumen and a second lumen. In some cases, the method also includes delivering the mixture through the first lumen, and delivering microcoils through the second lumen. 
     In another aspect, this disclosure is directed to a needle assembly for providing treatment to a patient. The needle assembly includes a needle housing defining a breakaway region, and a needle enclosed in the needle housing. The breakaway region exposes a portion of the needle. In some cases, the portion of the needle exposed by the breakaway region has a length to receive wire cutters. In some cases, when a force is applied on either side of the breakaway region, the portion of the needle exposed by the breakaway region breaks. In some cases, the needle includes multiple lumens. In some cases, the needle defines an inner lumen with a coating. In some cases, the coating is at least one of an anticoagulant, a lipid-based agent, an acetone, or a nitromethane. In some cases, the needle is configured to deliver a mixture to a targeted area of the patient. In some cases, the mixture includes a therapeutic agent, a glue, and a radiopaque substance. In some cases, the therapeutic agent is a chemotherapeutic agent. In some cases, the glue is a cyanoacrylate. In some cases, the radiopaque substance is a lipid-based agent. In some cases, the mixture further includes at least one of a nanoparticle, an alcohol, an anesthetic agent, a radioactive material, a vasoconstricting agent, a vasodilating agent, an ultrasound contrast medium, a ultrasound microbubble, an anti-stromal agent, a pathway inhibitor, an immunotherapy agent, a vaccine, or a combination thereof. 
     Particular embodiments of the subject matter described in this document can be implemented to realize one or more of the following advantages. First, the devices and methods provided herein can provide new systemic and targeted therapies impacting both tumor cells and the associated microenvironment and means of precision delivery are provided to improve local tumor control and to work in synergy with bespoke individualized therapies to customize patient care and outcome. Second, the chemotherapy diffusion pattern and extent for endoscopic ultrasound fine needle injection (EUS FNI) can abide by different principles than systemically delivered drugs. Third, local injection can allow delivery of greater drug concentrations and anti-stromal agents, thereby overcoming protective mechanisms developed by neoplastic cells and the microenvironment. Fourth, by increasing the intratumoral dose of chemotherapy or delivering a targeted agent based on the molecular landscape of the tumor and/or an anti-stromal agent, the therapeutic efficacy can be enhanced and the risk of adverse events can be reduced. Fifth, many patients, with a variety of tumors, such as those discussed above, can benefit from the local therapy. Sixth, many non-pancreatic solid and cystic lesions located within and remote to organs can benefit from local targeted therapy. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and not intended to be limiting. 
     The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description, drawings, and from the claims. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  is a perspective view of a proximal portion of an endoscope with a needle assembly attached, in accordance with some embodiments provided herein. 
         FIG. 2  is a close-up perspective view of a proximal portion of an endoscope with a needle assembly attached, in accordance with some embodiments provided herein. 
         FIG. 3  is a perspective view of a distal portion of an endoscope with a needle assembly, in accordance with some embodiments provided here. 
     
    
    
     Like reference numbers represent corresponding parts throughout. 
     DETAILED DESCRIPTION 
     This document describes methods and materials for improving cancer treatment. For example, this document describes methods and devices for local tumor control and customizable patient treatment. 
     Chemotherapy and radiation therapy have been used to treat pancreatic ductal adenocarcinoma (PDAC). However, the median survival expectancy for locally advanced pancreatic cancer (LAPC) remains at only 9-11 months, even with administration of chemoradiotherapy, and at only 6 months for patients with metastatic disease. Neoadjuvant therapy is routinely administered to patients with LAPC with the aim of tumor downstaging to potentially allow subsequent resection. The limited efficacy of conventional PDAC therapy results from the tumor biology, severe desmoplasia and altered tumor induced biophysical properties that result in neoplastic islands interspersed among dense stroma. This resulting tumor structure topography alters the pattern and limits chemotherapy penetrance to the tumor. 
     The devices and methods provided herein can provide new systemic and targeted therapies impacting both tumor cells and the associated microenvironment. In addition, means of precision delivery are provided to improve local tumor control that work in synergy with bespoke individualized therapies to customize patient care and outcome. The local injection can allow delivery of greater drug concentrations and anti-stromal agents, thereby overcoming protective mechanisms developed by neoplastic cells and the microenvironment. By increasing the intratumoral dose of chemotherapy or delivering a targeted agent based on the molecular landscape of the tumor and/or an anti-stromal agent, the therapeutic efficacy can be enhanced, and the risk of adverse events can be reduced. 
     Referring to  FIGS. 1-3 , an example endoscope  100  can include a control head  102  and a body  104 . In some cases, control head  102  can include an up/down knob  108 , an up/down lock  110 , a left/right knob  112 , a left/right lock  114 , a first button  116 , a second button  118 , and/or cable  120 . In some cases, body  104  can include a body portion  130 . 
     Up/down knob  108  can provide actuation of a distal portion (e.g., a bending portion) of endoscope  100  in a first plane. For example, up/down knob  108  can provide actuation in two directions within the first plane. Optionally, up/down knob  108  can provide actuation of the distal portion by mechanical means. For example, up/down knob  108  can provide actuation of the distal portion of the endoscope  100  by rotating a chain and sprocket on a gear that can be attached to angulation wires that extend to the distal portion of the endoscope  100 . In some cases, the angulation wires can be attached to rings and pivot pins, such that rotation of the up/down knob  108  causes the distal portion to bend or move in a first direction and/or a second direction within the first plane. In another embodiment, up/down knob  108  can provide actuation of the distal portion by electrical means. For example, the up/down knob  108  can cause actuation of the distal portion via a motor. 
     Up/down lock  110  can prevent rotation of the up/down knob  108  when up/down lock  110  is engaged. In some cases, up/down lock  110  can cause previous rotation of the up/down knob  108 , and therefore actuation of the distal portion of the endoscope  100 , to be locked into place such that the position of the distal portion is maintained. Optionally, when up/down lock  110  is disengaged, up/down knob  108  can be rotated. Alternatively, when up/down lock  110  is disengaged, the position of up/down knob  108  can return to a neutral position (e.g., an original or starting position, such as a position that causes no bending of the distal end of endoscope  100 ). 
     Left/right knob  112  can provide actuation of a distal portion (e.g., a bending portion) of endoscope  100  in a second plane, different from the first plane, for example, in two directions within the second plane. Optionally, left/right knob  112  can provide actuation of the distal portion of the endoscope  100  by rotating a chain and sprocket on a gear that can be attached to angulation wires that extend to the distal portion of the endoscope  100 . In some cases, the angulation wires can be attached to rings and pivot pins, such that rotation of the left/right knob  112  causes the distal portion to bend or move in a first direction and/or a second direction within the second plane. Alternatively, left/right knob  112  can provide actuation of the distal portion by electrical means. For example, the left/right knob  112  can cause actuation of the distal portion via a motor. 
     Left/right lock  114  can prevent rotation of the left/right knob  112  when left/right lock  114  is engaged. In some cases, left/right lock  114  can cause previous rotation of the left/right knob  112 , and therefore actuation of the distal portion of the endoscope  100 , to be locked into place such that the position of the distal portion is maintained. In some embodiments, when left/right lock  114  is disengaged, left/right knob  112  can be rotated. Alternatively, when left/right lock  114  is disengaged, the position of left/right knob  112  can return to a neutral position (e.g., an original or starting position, such as a position that causes no bending of the distal end of the endoscope  100 ). 
     First button  116  and/or second button  118  can be valves. For example, first button  116  and/or second button  118  can be a suction valve, an air valve, a water valve, an anti-reflux valve. In some cases, first button  116  and/or second button  118  can include a vent hole. Optionally, first button  116  and/or second button  118  can be remote switches. For example, first button  116  and/or second button  118  can control a light (e.g., turning the light on and/or off), a camera (e.g., turning the camera on and/or off), or a similar device or feature. In some cases, first button  116  and/or second button  118  can be removable, for example, for cleaning. In some cases, first button  116  and/or second button  118  can be electronic switches that can control valves, pumps, or other devices of the endoscope  100 . The control valves can interact with various channels of the endoscope  100 . Optionally, the control valves can interact with various channels of the endoscope  100  without coming into contact with the fluids (e.g., gases and/or liquids) inside the channels. For example, a mechanical pump can surround the channel and vary a pressure around the channel to cause pumping. 
     Cable  120  can be coupled to the other portions of control head  102  of endoscope  100  and can provide means of connection to an external electronic device, such as an endoscopy tower (not shown). The endoscopy tower can include an electronic control valve, such as an air control valve and/or a water control valve. In some cases, the endoscopy tower can include a video image processor that can receive video information from a camera located at a distal end of the endoscope  100 . Optionally, the endoscopy tower can provide imaging, such that a user can view images and/or video via the camera. The endoscopy tower can also allow a user to modify parameters of the video or image, such as contrast, brightness, zoom, etc. 
     In some cases, body portion  130  can taper, or decrease in diameter as body portion  130  extends away from control head  102 . Body portion  130  can provide additional features and/or components of endoscope. For example, body portion  130  can include a valve  140  that can provide access from body portion  130  to a distal end of endoscope  100 . In some cases, valve  140  can be positioned at an angle from the body portion  130  such that inserting a tool into valve  140  can be made easier based on the angle between the valve  140  and the body portion  130 . Optionally, valve  140  can include a cap, or deflectable valve, such that when a biopsy tool is not being used, valve  140  remains closed to reduce the chance of infection, cross contamination, or spread of other bacteria. In some cases, valve  140  can include means for securing or attaching a tool to valve  140 , and accordingly, body portion  130 . For example, valve  140  can be a luer lock. 
     In some cases, body portion  130  can include a tube  106  (shown in  FIG. 3 ) that can be inserted into a patient. In some cases, tube  106  can be made of metal and/or plastic. In some cases, tube  106  can include a bending section. In some cases, the bending section can be located at a distal portion of tube  106 . In some cases, tube  106  can be deformable. In some cases, tube  106  can provide access from a proximal portion (e.g., control head  102  and/or body  104 ) to a distal end of the endoscope  100 . In some cases, tube  106  can provide access for control elements, channels, and/or other components of endoscope  100 . 
     Tube  106  can include a distal portion  122 . Distal portion  122  can include an ultrasound head  124 . Ultrasound head  124  can include a transducer (not shown). In some cases, the transducer can be a linear transducer such that ultrasound images captured are parallel to endoscope  100 . In some cases, the transducer can be a radial transducer such that ultrasound images captured are perpendicular to endoscope  100 . In some cases, the transducer can be front viewing at the tip (rather than side) of endoscope  100 . In some cases, ultrasound head  124  can include a camera such that a user can direct endoscope  100  to a desired location. In some cases, ultrasound head  124  can include a light source to aid in directing endoscope  100  to a desired location. In some cases, ultrasound head  124  can include other devices/features such as apertures, channels, or nozzles. 
     As shown in  FIGS. 1-3 , the valve  140  can receive a needle assembly  200 . Needle assembly  200  can include a needle housing  204  and a needle  206 . Needle housing  204  can include a valve coupling region  202  and a breakaway region  208 . 
     In some cases, needle  206  can include a coating along an inner lumen of needle  206 . For example, the inner lumen can be coated with an anticoagulant (e.g., to reduce the risk of clot formation), a lipid-based agent or other fatty solvent (e.g., to reduce polymerization of a glue and prevent occlusion of the inner lumen of needle  206  by the glue), a acetone or nitromethane (e.g., to reduce polymerization of a glue and prevent occlusion of the inner lumen of needle  206  by the glue), or a combination thereof. 
     In some cases, the instrument channel can be coated with an agent. For example, the instrument channel can be coated with an anticoagulant (e.g., to reduce the risk of clot formation), a lipid-based agent or other fatty solvent (e.g., to reduce polymerization of a glue and prevent occlusion of the instrument channel by the glue), an acetone or nitromethane (e.g., to reduce polymerization of a glue and prevent occlusion of the instrument channel by the glue), or a combination thereof. 
     In some cases, needle  206  can include multiple lumens (e.g., two or three lumens). In some cases, multiple lumens can be used such that different agents, in different lumens, are injected at different injection rates. In some cases, multiple lumens can inject different agents at different times, allowing for varying exposure times. In some cases, multiple lumens can be used to deliver a first inactive agent and a second inactive agent separately, such that the combination of the first inactive agent and the second inactive agent causes activation of the agents. In some cases, a final injection of a liquid or physical sealant can be used to prevent retrograde diffusion of the injected agent along the needle track. 
     In some cases, multiple lumens can be used to inject microcoils through a first lumen and a liquid agent through a second lumen, eliminating the need to remove needle  206  and insert a second needle. Optionally, the microcoils can be embedded with various agents. For example, the microcoils can be embedded with a glue, a lipid-based agent, a hemostatic agent, a chemotherapeutic agent, a radiosensitive agent, an anti-stromal agent, or a combination thereof. 
     In some cases, needle  206  can have an outer diameter that is sufficiently large enough to occupy substantially all the space within the instrument channel. Such a diameter can reduce reflux of blood clots, glue, or other materials which could damage endoscope  100 , and can negatively impact imaging. In some cases, needle  206  can have an increased diameter by using an inflatable balloon that can be inflated at a distal portion of the instrument channel. In addition, the inflatable balloon can aid in maintaining needle  206  in a center of the instrument channel, and in a correct plane. In some cases, needle  206  can have an increased diameter by using a thicker outer sheath for needle  206 . In some cases, needle  206  can have an increased diameter by using struts. 
     In some cases, needle tip  212  can include an inflatable balloon. For example, the inflatable balloon can be inflated once needle tip  212  is advanced into the vessel or duct (e.g., bile duct or pancreatic duct), or fluid collection to help safely hold needle  206  in place. In some cases, the inflatable balloon can be configured such that when inflated, the inflatable balloon overlies needle tip  212 , to provide increased safety, for example. 
     Breakaway region  208  can provide an exposed region of needle  206 . In some cases, breakaway region  208  allows needle  206  to be cut or broken at a proximal end of needle  206 , and a proximal end of endoscope  100 . In some cases, breakaway region  208  can be sized to allow a wire cutter to reach needle  206 , such that needle  206  can be cut. In some cases, breakaway region  208  can be sized to prevent a wire cutter from reaching needle  206 . In some cases, needle  206  can be broken by applying force on a proximal region of needle assembly  200  and valve coupling region  202 . By cutting or breaking needle  206  at a proximal portion of needle  206 , an amount of glue, agents, or other fluids that are retracted into the instrument channel can be reduced, while increasing safety of a user by reducing the risk of a needle stick. For example, needle tip  212  can be retracted into the instrument channel, or into a needle sheath inside the instrument channel, such that needle tip  212  is no longer exposed distal to the instrument channel. Endoscope  100  can be removed from the patient, with needle  206  being removed as well. Once removed, needle  206  can be cut or broken at breakaway region  208 , such that distal portion  210  and needle tip  212  can be removed from a distal portion of the instrument channel, while a proximal portion of needle  206  can be removed from valve  140 . Such a removal process can reduce an amount of glue, agents, or other fluids from entering, and potentially occluding, the instrument channel. In some cases, breakaway region  208  can also include means for securing needle  206 . For example, breakaway region  208  can have an adapter configured to secure needle  206  such that needle tip  212  protrudes from the instrument channel a desired amount, or such that needle tip  212  is securely within the instrument channel. 
     While the devices and methods herein have been described with respect to an endoscope, various other modalities may be used to administer therapy. For example, endoscopic ultrasound, standard endoscopy, interventional radiology guided delivery, and via percutaneous routes. 
     Further, in some cases, the devices and methods described herein can be used to perform and provide additional treatments. For example, endoscopic ultrasound delivery of an inferior vena cava filter to inhibit clot embolization can be performed. As another example, endoscopic ultrasound delivery of vascular stents can be performed. 
     Delivery Agent 
     In some cases, a delivery agent may be used in conjunction with the needle assembly  200 . For example, the therapeutic agent that is being administered to the patient may include a glue and/or a lipid-based agent, or other radiopaque liquid substance. In some cases, the glue is a cyanoacrylate (e.g., Dermabond). In some cases, the therapeutic agent may be a chemotherapeutic. Some advantages of using a glue and/or a radiopaque liquid substance as a delivery agent are as follows. First, the viscosity of the delivery compound delivered can be easily altered to obtain an ideal viscosity. Second, the compound can allow diffusion of the therapeutic agent throughout solid and cystic lesions. Third, imaging modalities (e.g., fluoroscopy, endoscopic ultrasound, etc.) can be used to easily observe a pattern and extent of spread of the therapeutic agent. Fourth, the compound, and therefore the therapeutic agent, can remain within the target site for prolonged periods of time, allowing for increased durability of the treatment. Fifth, a collateral benefit can include vascular compromise with diminished blood flow and cellular death (e.g., of cancerous cells). In some cases, the glue, lipid-based agent, and/or therapeutic agent compound can also be combined with nanoparticles, alcohol, anesthetic agents, radioactive materials, vasoconstriction agents, vasodilating agents, ultrasound contrasts (e.g., to aid with visualization), ultrasound microbubbles (e.g., containing other agents described herein), anti-stromal agents (e.g., to break down fibrosis), targeted therapy based on a molecular signature of the tumor (e.g., mammalian target of rapamycin (mTOR) or poly ADP ribose polymerase (PARP) pathway inhibitors), immunotherapy agents, a vaccine, or a combination thereof. In some cases, an injectant can also serve as a radiopaque, possibly biodegradable, liquid fiducial to facilitate proton and photon radiation therapy. 
     Target Lesions 
     Numerous targets, pathologies, and therapies can benefit from the devices and methods described herein. For example, solid pancreatic tumors may include PDAC, functioning and non-functioning neuroendocrine tumors, lymphoma, second metastasis to the pancreas, etc. There are also several cystic pancreatic tumors (CPT) such as intraductal papillary mucinous neoplasia, mucinous cystic neoplasia, and serous cystadenomas, among others, that would benefit from local therapy. Similarly, many non-pancreatic solid and cystic lesions located within and remote to organs may benefit from local targeted therapy. Targets also include various types of bleeding lesions such as varices (esophageal, gastric, anastomotic, etc.), ulcers (gastroduodenal, etc.), pseudoaneurysms (splenic artery, etc.), etc. 
     While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any invention or of what may be claimed, but rather as descriptions of features that may be specific to particular embodiments of particular inventions. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub combination. Moreover, although features may be described herein as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub combination or variation of a sub combination. 
     Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Moreover, the separation of various system modules and components in the embodiments described herein should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single product or packaged into multiple products. 
     Particular embodiments of the subject matter have been described. Other embodiments are within the scope of the following claims. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results. As one example, the process depicted in the accompanying figures does not necessarily require the particular order shown, or sequential order, to achieve desirable results. In certain implementations, multitasking and parallel processing may be advantageous.