US20080161744A1 - Pre-And Intra-Operative Localization of Penile Sentinel Nodes - Google Patents
Pre-And Intra-Operative Localization of Penile Sentinel Nodes Download PDFInfo
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- US20080161744A1 US20080161744A1 US11/851,312 US85131207A US2008161744A1 US 20080161744 A1 US20080161744 A1 US 20080161744A1 US 85131207 A US85131207 A US 85131207A US 2008161744 A1 US2008161744 A1 US 2008161744A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
Definitions
- a variety of medical techniques suitable for imaging biological tissues and organs are known. These include traditional x-rays, ultra-sound, magnetic resonance imaging, and computerized tomography.
- a variety of dyes useful for medical imaging have been described, including radio opaque dyes, fluorescent dyes, and colorimetric dyes (see e.g., U.S. Pat. Nos. 5,699,798; 5,279,298; 6,351,663). Imaging techniques and systems using fluorescent dyes have been described for the heart and eye (see, e.g., U.S. Pat. No. 5,279,298). Some dyes can serve both an imaging function and a therapeutic function (see, e.g. U.S. Pat. No. 6,840,933). Some specific neuronal imaging agents have been used to visualize tissue in the central nervous system.
- tracers were visually detected using ultraviolet or visible light (Bentivoglio et al., 1980, Neurosci Lett. 18(1):19; Minciacchi D et al., 1991, J Neurosci Methods. 38(2-3):183). Tracers such as Indocyanine Green, Fast Blue, and Fluorogold, have been used in mammals without evidence of neuronal toxicity several months after the treatment (Thielert et al., 1993, J Comp Neurol. 337(1):113; Yeterian et al., 1994, Exp Brain Res.
- Marangos et al. labeled the auditory nerve using Fluorogold and Fast Blue in rats and monkeys by suctioning out perilymph and filling the cochlea with neuronal tracers to identify the nerve and cochlear brain stem nucleus for the positioning of electrodes for an auditory neuroprosthesis (Marangos N, et al., 2001, Hear Res. 162(1-2):48).
- penile cancers are squamous cell carcinomas and usually develop on the foreskin (if the male is uncircumsized) or the glans.
- the patient presents with a rash, bumps, ulcer or discharge, and the cancer is diagnosed by microscopic examination of biopsied tissue. Lymph node metastasis is a crucial prognostic factor in penile cancer.
- SLND sentinel lymph node dissection
- Penis American Joint Committee on Cancer, AJCC Cancer Staging Manual, 6th Ed., Springer, NY N.Y., 2002, pp. 302-8.
- the invention provides methods of localizing before or during a surgical operation a lymph node draining a penile tumor having edges and a base in a subject, comprising, about 10 minutes to about 24 hours prior to the surgical operation, injecting the edges or the base of the tumor of the subject with a dye which fluoresces at an emission wavelength when the dye is contacted with an excitation wavelength; exposing the lymph node to illumination comprising the excitation wavelength, thereby causing the fluorescent dye to fluoresce; and, detecting the fluorescence of the dye, thereby localizing the lymph node.
- the lymph node is a sentinel lymph node.
- the dye is injected into the edges of the tumor.
- the dye is injected into the base of the tumor.
- the lymph node is visualized on a image display.
- the exposure of the lymph node to excitation wavelength is by a laparoscopic instrument.
- the dye is a dye which fluoresces when exposed to near infrared light.
- the dye is a tricarbocyanine dye or an analog thereof.
- the tricarbocyanine dye is indocyanine green.
- the subject is a human.
- the dye is injected between about 10 minutes and 12 hours before the surgical operation. In some embodiments, the dye is injected between about 1 hour and about 6 hours before the surgical operation.
- the dye is injected between about 1 hour and about 2 hours before the surgical operation.
- the steps of exposing the lymph node to illumination comprising the excitation wavelength, thereby causing the fluorescent dye to fluoresce; and detecting the fluorescence of the dye, thereby localizing the lymph node are performed during the surgical operation.
- the surgical operation is a laparoscopic operation.
- FIG. 1 shows detection of inguinal lymph nodes by near infrared fluorescence (NIRF) through the body wall of a rat in which indocyanine green had been injected into the cavernous bodies of the penis. Arrows indicate the lymphatics and the lymph nodes.
- NIRF near infrared fluorescence
- FIG. 2 shows an intraoperative image of inguinal lymph nodes first detected by near infrared fluorescence (NIRF) through the body wall of a rat in which indocyanine green had been injected into the cavernous bodies of the penis. Arrows indicate the lymphatics and the lymph nodes.
- NIRF near infrared fluorescence
- Lymph nodes that receive the lymph from a particular organ or region of the body are considered to “drain” that organ or region.
- various techniques and agents have been used to try to detect the lymph nodes draining penile cancers. Unfortunately, all suffer from various problems, such as exposing the patient to radioactivity, and none have emerged as a standard of care.
- a tumor can be considered to have both edges, defining the lateral borders of the tumor, and a base, defining the depth to which the tumor has invaded into the tissue and structures of the penis.
- the lymph nodes draining the cancer can be localized and visualized by injecting the edges or base of the tumor, or preferably, both, with a non-toxic, fluorescent dye.
- the injections will be in the glans, while a tumor in the prepuce (more familiarly known as the foreskin), the injections will be into the prepuce.
- a tumor in the prepuce more familiarly known as the foreskin
- injections are made into the base of the tumor in the affected corpus cavernosum.
- corpus cavernosum is the singular form and “corpora cavernosa” is the plural form.
- the corpora cavernosa will sometimes be referred to herein as the “cavernous bodies.”
- the ability to locate and visualize nodes can be referred to as “localizing” the nodes.
- the dye injections are typically about 30 to 300 ⁇ l each, more preferably about 50 to about 200 ⁇ l, still more preferably about 60 to about 175 ⁇ l, more preferably about 75 to about 150 ⁇ l, more preferably about 90 to about 125 ⁇ l each, more preferably about 100 ⁇ l, and most preferably 100 ⁇ l each, with “about” in this context meaning plus or minus 15 ⁇ l.
- “about” in this context meaning plus or minus 15 ⁇ l.
- Urologic surgeons are considered to be familiar with the criteria for staging penile cancers, which are based in part on the extent to which the tumor has invaded the tissue; selecting a suitable number of injections for tumors of different sizes is considered to be within the skill of the practitioner.
- ICG indocyanine green
- dye injections can be made as soon as the patient is in the operating room and under anesthesia. To minimize the duration of use of the operating room and surgical team, however, the injections will more typically be given pre-operatively.
- Patients are, typically prepared for penile cancer surgery in a pre-anesthesia room an hour or two before the surgery, during which time they are given mild sedation or a calming medication.
- the dye injections are made after the sedative has taken effect to reduce the patient's discomfort at receiving small penile injections.
- lymph nodes could be seen through the body wall for days after injection; however, in the context of detecting and visualizing sentinel nodes, periods as long as 24 hours may permit the dye to disperse to more distal lymph nodes.
- the dye 12 hours or less before the surgical operation, with 11, 10, 9, 8, 7, 6, 5, 4, 3, and 2 hours being successively more preferred.
- the dye is administered about 1 to 2 hours before the operation, with “about” in this context meaning one-half hour on either side of the designated time.
- the dye is injected about 1 hour before the operation, with “about” in this context meaning plus or minus 15 minutes, permitting the dye to reach the sentinel nodes while minimizing the dispersion to more distal nodes.
- FIG. 1 shows fluorescence in a rat injected in the cavernous bodies with ICG. Arrows point to the lymphatic channels and to the lymph nodes. More than one sentinel nodes were visualized in two rats. No fluorescence was seen in control animals injected with saline. Intraoperative observations confirmed the preoperative localization of the inguinal nodes. All lymph nodes were confirmed by conventional histological review.
- FIG. 2 shows an intraoperative image of left inguinal lymph nodes following injection of ICG into the cavernous bodies.
- fluorescent dyes have a particular excitation wavelength which causes the dye to fluoresce and emit light of a particular emission wavelength.
- excitation wavelength causes the dye to fluoresce and emit light of a particular emission wavelength.
- emission wavelength causes the dye to fluoresce and emit light of a particular emission wavelength.
- the methods described herein are suitable for use in mammals.
- mammals for which the techniques can be used include, but are not limited to, non-human primates, dogs, cats, sheep, cows, pigs, horses, and rabbits.
- the methods are particularly useful in visualizing lymph nodes in humans, and particularly the lymph nodes draining the penis in humans.
- the penis can be thought of as comprising three cylinders. Two, the corpora cavernosa, are disposed on either side of the penis, and make up the bulk of the penis. The third, the corpus spongiosum, which contains the urethra, is disposed in the middle of the penis, in a cleft between the undersides of the corpora cavemosa. A “deep artery” runs down the center of each corpus cavernosum and provides blood to sinusoidal spaces in the respective corpus. The end of the penis distal to the body ends in the glans penis which, in uncircumcised males, is protected by the prepuce.
- N.Y. National Cancer Institute
- the NCI website notes with regard to stage 0 cancer, that carcinoma in situ of the penis is referred to as erythroplasia of Queyrat when it occurs on the glans, and Bowen's disease when it occurs on the penile shaft. These precursor lesions progress to invasive squamous cell carcinoma in 5% to 15% of cases.
- the NCI website notes that surgical excision can result in scarring, deformity, and impaired function, and that Mohs micrographic surgery, which involves the excision of successive horizontal layers of tissue with microscopic examination of each layer in frozen section, has been developed for use in patients with in situ and invasive penile cancers. See, e.g., Mohs et al., J. Urol. 133(6): 961-6 (1985).
- the NCI website states that, for lesions limited to the foreskin, wide local excision with circumcision may be adequate therapy for control.
- wide local excision with circumcision may be adequate therapy for control.
- the choice of therapy is dictated by tumor size, extent of infiltration, and degree of tumor destruction of normal tissue.
- equivalent therapeutic options include: penile amputation, radiation therapy (i.e., external-beam radiation therapy and brachytherapy), and microscopically controlled surgery.
- lymph nodes in conjunction with amputation are often used for patients with poorly differentiated tumors. Lymphadenectomy, however, can carry substantial morbidity, such as infection, skin necrosis, wound breakdown, chronic edema, and a low, but finite, mortality rate.
- the NCI indicates that the impact of prophylactic lymphadenectomy on survival is not known.
- stage II penile cancer is most frequently managed by penile amputation for local control. Whether the amputation is partial, total, or radical will depend on the extent and location of the neoplasm. External beam radiation therapy and brachytherapy with surgical salvage are alternative approaches.
- the NCI site further states that inguinal adenopathy in patients with stage III penile cancer is common but may be the result of infection rather than neoplasm.
- the website further states that, if palpable enlarged lymph nodes exist 3 or more weeks after removal of the infected primary lesion and completion of a course of antibiotic therapy, bilateral inguinal lymph node dissection should be performed.
- the methods of the present invention can be performed to assist in dissection of the nodes. Since, in this case, the primary lesion has been removed, the injections are of course made into the cavernous bodies. In cases of proven regional inguinal lymph node metastasis without evidence of distant spread, bilateral ilioinguinal dissection is the treatment of choice.
- the NCI notes that there is no curative standard treatment. Therapy is directed at palliation, which may be achieved either with surgery or radiation therapy.
- the standard treatment options include palliative surgery for control of the local penile lesion and palliative radiation therapy for the primary tumor, regional adenopathy, and bone metastases.
- the device used for visualization comprises both a laser and a camera.
- the discussion below refers to the exemplar dye ICG.
- the laser conveniently consists of a laser diode providing a maximum of 3 W output at 806 nm.
- the laser diode is selected to provide a light with a wavelength at an excitation frequency appropriate for the dye selected.
- the laser output is decollimated (i.e. optics are used to spread out the laser light from a tight beam) to provide even illumination over a field of view, for example, 7.6 cm by 7.6 cm at a working distance of 30 cm.
- the imaging system typically has a camera containing a charge-coupled device (“CCD”) or a complementary symmetry metal oxide semiconductor (“CMOS”) image sensor sensitive into the near infrared spectrum and, for use with ICG, is equipped with an 815 nm edge filter.
- the laser or camera or both are supported by an articulated arm connected to a wheeled base. This allows the imaging head to be moved into close proximity to the surgical table and for vertical movement of the head to attain an appropriate focal distance above the area of interest.
- the imaging head and extension arm that protrudes over the surgical field are typically covered with an optically transparent sterile drape.
- the laser can conveniently be activated by means of a computer command or by foot pedal.
- Laser/camera devices suitable for intra-operative imaging are commercially available.
- the laser/camera device is a SPY® Intra-operative Imaging System, a HELIOS® Imaging System, or a LUNA® Imaging System (all by Novadaq Technologies, Inc., Mississauga, Ontario, Canada).
- an instrument having an optical configuration similar to a fluorescence microscope may be used, in which a dichroic mirror is used to split the paths of the illumination (the excitation light).
- the excitation light reflects off the surface of the dichroic mirror into the objective, while the fluorescence emission passes through the dichroic mirror to the eyepiece or is converted into a signal to be presented on a screen.
- the instrument may further have an excitation filter or an emission filter, or both, to select the wavelengths appropriate for each function.
- the filters are interference filters, which block transmission of frequencies out of their bandpass.
- the ICG is administered by injection into the cavernous bodies, preferably into the crura, permitting the dye to be transported through the lymphatic channels serving the area to the sentinel node or nodes.
- a 806 nm excitation light causes the dye to fluoresce, emitting light at 830 nm.
- the emitted light can then be imaged directly or, preferably, is captured using an imaging system.
- the capture system is typically a video camera containing a CCD or CMOS image sensor.
- the capture system feeds the image to a monitor so that the surgeon can visualize the fluorescence of the dye in the lymph nodes in the area of interest in real time. Filters limit the light detected to a range appropriate for the selected fluorescence wavelengths.
- the camera is also attached to a computer and the image is saved, which not only permits documentation of the extent to which the tumor or tumors, but also can be used for training urologic surgeons, nurses, and other medical staff.
- the time required for positioning the device is 2 minutes, while the total time that the vessels are illuminated with laser light is 30 seconds.
- suitable mammals include, but are not limited to, humans, non-human primates, dogs, cats, sheep, cows, pigs, horses, mice, rats, rabbits, and guinea pigs. Use in humans is primates, and particularly in humans, is preferred.
- fluorescent dyes have a particular excitation wavelength which causes the dye to fluoresce and emit light of a particular emission wavelength.
- Persons of skill will appreciate that a considerable literature is available in the art on the characteristics of different dyes, including their excitation wavelength and emission wavelength. This literature is well known, and will not be set forth in detail herein.
- the dye is imaged by exciting it with a light that has an excitation wavelength appropriate for the particular dye used.
- a light that has an excitation wavelength appropriate for the particular dye used.
- Some dyes for example, fluoresce under ultraviolet (“UC”) illumination while others fluoresce under incandescent illumination.
- UC ultraviolet
- the literature on the use of fluorescent dyes and probes in biological assays includes, for example, Dewey, T. G., Ed., Biophysical and Biochemical Aspects of Fluorescence Spectroscopy, Plenum Publishing (1991), Guilbault, G. G., Ed., Practical Fluorescence, Second Edition, Marcel Dekker (1990), Lakowicz, J.
- the dye selected is one that has low toxicity and has excitation and emission peaks within the “optical window” of tissue, where absorption due to endogenous chromophores is low.
- Preferred fluorescent dyes suitable for use in the methods of the invention are non-toxic dyes which fluoresce when exposed to radiant energy, e.g. light.
- the dyes are near infrared fluorochromes, or “NIRF” that emit light in the near infra red spectrum. Near infrared light can penetrate tissue to a depth of several millimeters to a few centimeters.
- the dye is a tricarbocyanine dye, and in particularly preferred embodiments, is ICG.
- the dye is selected from fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, fluorescamine, Rose Bengal, trypan blue, and fluoro-gold.
- the dyes may be mixed or combined.
- dye analogs may be used.
- a “dye analog” is a dye that has been chemically modified, but still retains its ability to fluoresce when exposed to radiant energy of an appropriate wavelength.
- ICG Intravenous calfrared spectroscopy
- FCG Fluorogold
- ICG is particularly preferred both because it has low toxicity and because it has been approved by the Food and Drug Administration for several diagnostic purposes in humans.
- its absorption (excitation) and emission peaks (805 and 835 nm, respectively) lie within the “optical window” of tissue.
- ICG is commercially available from, for example, Akorn, Inc. (Buffalo Grove, Ill.), which sells it under the name IC-GREENTM.
- IC-GREENTM After intravenous injection, ICG is bound within 1 to 2 seconds, mainly to globulins (1-lipoproteins), and remains intravascular, with normal vascular permeability.
- ICG is not metabolized in the body and is excreted exclusively by the liver, with a plasma half-life of 3 to 4 minutes. It is not reabsorbed from the intestine and does not undergo enterohepatic recirculation.
- the recommended dose for ICG video angiography is 0.2 to 0.5 mg/kg; the maximum daily dose should not exceed 5 mg/kg.
- the surgical field For intraoperatively visualizing the lymph nodes and channels, the surgical field, or the portion of the surgical field in which imaging is desired, is illuminated with a light of the excitation wavelength or wavelengths suitable for the dye or dyes used. Since the channels are thin and the nodes are small (accounting in part for the difficulty in discerning them with the unaided eye), ambient light may need to be dimmed to permit the fluorescence to be seen. Observation will typically also require magnification. Where the excitation wavelength is outside of the visible range (where, for example, the excitation wavelength is in the ultraviolet or near infrared range), the light source may be designed to permit switching or “toggling” between the excitation wavelength and visible light. This permits the practitioner to note the position of the node or nodes using the fluorescent property in relation to the rest of the surgical field and surrounding (but non-fluorescent) structures.
- an instrument having an optical configuration similar to a fluorescence microscope may be used, in which a dichroic mirror is used to split the paths of the illumination (the excitation light).
- the excitation light reflects off the surface of the dichroic mirror into the objective, while the fluorescence emission passes through the dichroic mirror to the eyepiece or is converted into a signal to be presented on a screen.
- the instrument may further have an excitation filter or an emission filter, or both, to select the wavelengths appropriate for each function.
- the filters are interference filters, which block transmission of frequencies out of their bandpass.
- the dye is typically administered by an injection into one or both of the corpora cavernosa. Typically, the dye will be administered some hours preoperatively, to permit the dye to be transported to the nodes in the area of interest prior to commencing the surgical operation.
- the dye may be administered in the patient's room.
- the dye is administered sufficiently before the intended surgery to permit the dye to flow to the sentinel nodes draining the tumor area, but not so long before the surgery that the dye has been cleared from the nodes. Since the nodes could be detected through the body wall of the animals from 2 hours to 7 days after injection, it appears that the dye can be administered at the convenience of the patient and the practitioner from 2 hours up to a week before the intended surgery.
- a patient presenting with penile cancer will be injected with the dye no more than a few days before surgery is contemplated, since delay in performing the surgery will rarely be to the patient's benefit.
- the dye is administered at least about 2 hours but not more than 72 hours before the intended surgery. In some embodiments, the dye is administered at least about 2 hours but not more than 48 hours before the intended surgery. In other embodiments, the dye is administered at least about 2 hours but not more than 36 hours before the intended surgery. In preferred embodiments, the dye is administered between about 2 hours to 24 hours before the intended surgery. In still preferred embodiments, the dye is administered between about 2 hours to about 14 hours before the intended surgery, with “about” meaning a half hour on either side.
- Whether the patient has been injected too recently to provide adequate time for the dye to drain to the lymph nodes (for example, a half hour after injection, the dye would not yet be expected to have drained sufficiently to the nodes for optimal detection) can be readily determined pre-operatively by simply illuminating the groin with near infrared illumination under conditions permitting detecting any light emitted by the dye. If fluorescence is not sufficient to permit visualization of the nodes in the groin, a technician can simply reilluminate the area at half hour intervals or such other intervals as may be convenient until sufficient dye has drained to the sentinel lymph nodes to permit ready visualization.
- the maximum daily dosage of ICG for adults is 2 mg/kg. There is no data available describing the signs, symptoms, or laboratory findings accompanying an overdose of ICG.
- the LD 50 after IV administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats, and 50 to 80 mg/kg in rabbits.
- Intraoperative video angiography is performed with a laser-fluorescence imaging device (Novadaq Technologies, Inc., Mississauga, Ontario, Canada) consisting of a near infrared (NIR) laser light source and a NIR-sensitive digital camcorder.
- NIR near infrared
- the unit is positioned 30 to 40 cm from the area of interest.
- ICG dissolved in water
- the NIR light emitted by the laser light source induces ICG fluorescence.
- the fluorescence is recorded by a digital video camera, with optical filtering to block ambient and laser light so that, when desired, only ICG fluorescence is captured. Images can be observed on screen in real time (25-30 images/sec). The images can be reviewed and stored on the digital video camera or transferred to a computer or to storage media.
- Sprague-Dawley rats 60 to 100 days old, weighing 275-325 grams are used. All animals are anesthetized using intraperitoneal injection of Ketamine/Xylazine (40-80 mg/kg and 5/10 mg/kg, respectively) or isoflurane. No pre-anesthetic medications are used. When appropriate depth of anesthesia is reached, positioning of the animal takes place. All animals are fastened to a padded and heated restraint device in the supine position using gauze knots to fix all four extremities. Depth of anesthesia, regularity of respirations, and heart beat palpation are repeatedly checked. A pulse oximeter may be used to monitor the animal. Placebo (distilled water) or fluorochromes, ICG or Fluorogold, is administered by intra-penile, sub-albugineal injection of 25 ul of ICG diluted in 100 ⁇ l of water for injection, per cavernous body.
- Placebo distilled water
- fluorochromes ICG or Fluorogold
- Surgery/Procedure starts after appropriate preparation of surgical field by Povidone-Iodine scrub, 70% Isopropyl Alcohol and Povidone-Iodine solution.
- the surgical field includes the genital area, lower abdomen and perineum.
- the penis is squeezed out from the prepuce, then stretched using finger grip of the glans until maximally stretched; a clamp used for atraumatic clamping in neurosurgical operation on brain aneurysms is then placed at the root of the penis.
- This allows blood to pool inside the cavernous bodies, producing an erection and permitting easier application of a 27 Gauge butterfly needle to both sub-albugineal spaces. Adequate placement is assured when blood is easily aspirated.
- 0.5 mg/kg of ICG and 1 mg/kg of Fluorogold diluted in distilled water to total volume of 50 ⁇ l is injected, 25 ⁇ l per cavernous body.
- a placebo group is injected using 25 ⁇ l of distilled water per cavernous body.
- Animals in all groups have an exploratory laparotomy through midline lower incision, with intraoperative identification of nodes draining the penis. Midline incisions are made from umbilicus to pubis. Bowels and testicles after their release from scrotal attachments are packed back to upper abdomen. For better visualization of the pelvic structures, surgical loupes with 3.8 ⁇ magnification are used.
- Signs of acute pain are guarding (protecting the painful area), vocalization, especially when the animal moves or the painful area is touched, licking, biting, scratching or shaking a particular area, pacing, lack of mobility as seen with joint, colic or gut pain or an unusual gait posture during movement, failure to groom, causing an unkempt appearance, abnormal resting postures, loss of appetite or reduction in water consumption, and changes in behavior or signs of aggression.
- the rats undergo a second surgery (non-survival) and postmortem harvesting at chosen timepoints after fluorochrome injection.
- Anesthesia identical to the first procedure is administered and then appropriate skin preparation for surgery is performed.
- the same level of incision is used in second surgery/harvesting procedure.
- the bladder and prostate are exposed as in the first surgery.
- the penis is denuded of skin and the prepuce circumcised.
- the animal is euthanized by cardiac exsanguination. Death of the animal is confirmed using pulse oximeter and observation of complete absence of heart contractions.
- NIRF near infrared fluorescence
- Inguinal lymph node NIRF was detected through the body wall from 2 hours to 7 days after ICG injection ( FIG. 1 ). More than one pair of sentinel lymph nodes were visualized in 2 rats. No fluorescence was seen in controls. Intraoperative observations confirmed preoperative localization of all inguinal nodes ( FIG. 2 ). Inguinal and iliac sentinel lymph nodes were clearly visualized with NIRF, and were difficult to visualize otherwise. Lymphatic channels were seen leading to sentinel lymph nodes at 6, 12 and 24 hours ( FIG. 1 ). Lymphatic channels leading to the sentinel lymph nodes were seen in animals examined at 6, 12, and 24 hours post-injection of ICG. ( FIG. 1 ). All lymph nodes were confirmed by NIR microscopy and by conventional histology. Thus, NIR fluorescence using ICG facilitates both pre- and intraoperative identification of the first site of penile lymphatic drainage. The methods of the invention should therefore improve the accuracy of surgical staging in patients with penile carcinomas.
Abstract
Description
- This disclosure claims the benefit of U.S. Provisional Application No. 60/843,175, filed Sep. 7, 2006, the contents of which are incorporated herein by reference.
- NOT APPLICABLE
- NOT APPLICABLE
- A variety of medical techniques suitable for imaging biological tissues and organs are known. These include traditional x-rays, ultra-sound, magnetic resonance imaging, and computerized tomography.
- A variety of dyes useful for medical imaging have been described, including radio opaque dyes, fluorescent dyes, and colorimetric dyes (see e.g., U.S. Pat. Nos. 5,699,798; 5,279,298; 6,351,663). Imaging techniques and systems using fluorescent dyes have been described for the heart and eye (see, e.g., U.S. Pat. No. 5,279,298). Some dyes can serve both an imaging function and a therapeutic function (see, e.g. U.S. Pat. No. 6,840,933). Some specific neuronal imaging agents have been used to visualize tissue in the central nervous system. Tracer uptake and transport has been demonstrated in different studies using various routes of administration including antegrade, retrograde and combined routes (Jones et al. 1978, Annu Rev Neurosci., 1:215; Rosina A., 1982, Neurosci Lett. 33(3):217; Illing R B, et al., 1985, Neuroscience 14(2):455; Sloniewski P, et al., 1985, Neurosci Lett. 60(2):189; and Schmued et al., 1986, Brain Res. 377(1):147). After appropriate time for endo/pinocytosis, perineural lymphatic and axonal transport, which generally measures 0.5-2 mm per hour, tracers were visually detected using ultraviolet or visible light (Bentivoglio et al., 1980, Neurosci Lett. 18(1):19; Minciacchi D et al., 1991, J Neurosci Methods. 38(2-3):183). Tracers such as Indocyanine Green, Fast Blue, and Fluorogold, have been used in mammals without evidence of neuronal toxicity several months after the treatment (Thielert et al., 1993, J Comp Neurol. 337(1):113; Yeterian et al., 1994, Exp Brain Res. 99(3):383; vogt Weisenhorn et al., 1995, J Comp Neurol. 362(2):233). Marangos et al. labeled the auditory nerve using Fluorogold and Fast Blue in rats and monkeys by suctioning out perilymph and filling the cochlea with neuronal tracers to identify the nerve and cochlear brain stem nucleus for the positioning of electrodes for an auditory neuroprosthesis (Marangos N, et al., 2001, Hear Res. 162(1-2):48).
- According to the American Cancer Society, only some 1,500 cases are diagnosed a year in the U.S., accounting for only 0.2% of cancers in men in the U.S. Although penile cancer is relatively uncommon among American and European men, it is much more common in Africa and South America, where it accounts for 10% of all male cancers. While definitive causes of penile cancer are not known, there are some known risk factors. One such risk factor is infection with human papillomavirus. In a report available on-line as of this writing, Senba et al., J Med Virol. 2006, 78(10):1341-6, reported the detection of human papillomavirus DNA in 80% of 65 samples of penile cancer from That men, with HPV-18 being the most prevalent. Another, in uncircumcised males, is the buildup of secretions under the foreskin.
- According to the American Cancer Society, some 95% of penile cancers are squamous cell carcinomas and usually develop on the foreskin (if the male is uncircumsized) or the glans. Typically, the patient presents with a rash, bumps, ulcer or discharge, and the cancer is diagnosed by microscopic examination of biopsied tissue. Lymph node metastasis is a crucial prognostic factor in penile cancer. About 50% of patients with palpable lymph nodes will have metastases, and about 20% of patients without enlarged lymph nodes will have lymphatic spread (Hardner, G J, J Urol, 108:428ff (1972); Kossow, J H, Urology, 2:169ff (1973); McDougal, W S, J Urol 136:38ff (1986)). Successful sentinel lymph node dissection (SLND) is predicated on precise detection of the lymphatic drainage into sentinel nodes. According to the National Cancer Institute, when diagnosed early (stage 0, stage I, and stage II), penile cancer is highly curable, but curability decreases sharply for stage III and stage 1V. Criteria for staging penile cancer are known in the art, and set forth at, e.g., Penis: American Joint Committee on Cancer, AJCC Cancer Staging Manual, 6th Ed., Springer, NY N.Y., 2002, pp. 302-8.
- Unfortunately, there is significant anatomical variation in penile lymph node drainage as well as in sentinel lymph node position. In multiple cases, current dye or radionuclide lymphatic tracing methods result in identification of sentinel and some of the metastatic lymph nodes (Cabanas, R M, Urol Clin N Am 19:267ff (1992); Lynch, D F, Jr: AUA update series, 16:256 (1997)). Nevertheless these procedures are difficult, time-consuming, expensive and have low sensitivity, especially when used with methylene blue. If sentinel nodes are found without metastases this would obviate unnecessary removal of noninvolved nodes as seen in 90-95% of superficial lesions, 50-60% of T2 lesions, and 10-20% of T2b and T3 lesions (Horenblas et al., J Urol 155:1239-1243 (1994)). The presence of metastases will be followed by complete lymph node dissection. Current practice is to remove all inguinal or ilioinguinal lymph nodes in penile cancer surgeries, resulting in significant morbidity in more than 30% of the patients. Multiple methods, such as the use of radioactive tracers, have been used in the hope of improving the detection of sentinel nodes, see, e.g., Brennhovd et al., Sentinel node procedure in low-stage/low-grade penile carcinomas, Scand J Urol Nephrol. 2006; 40(3):204-7, but no method has yet emerged as a standard.
- Accordingly, a need exists for improved methods of locating sentinel lymph nodes for persons with penile cancer. The present invention fills these and other needs.
- The invention provides methods of localizing before or during a surgical operation a lymph node draining a penile tumor having edges and a base in a subject, comprising, about 10 minutes to about 24 hours prior to the surgical operation, injecting the edges or the base of the tumor of the subject with a dye which fluoresces at an emission wavelength when the dye is contacted with an excitation wavelength; exposing the lymph node to illumination comprising the excitation wavelength, thereby causing the fluorescent dye to fluoresce; and, detecting the fluorescence of the dye, thereby localizing the lymph node. In some embodiments, the lymph node is a sentinel lymph node. In some embodiments, the dye is injected into the edges of the tumor. In some embodiments, the dye is injected into the base of the tumor. In some embodiments, the lymph node is visualized on a image display. In some embodiments, the exposure of the lymph node to excitation wavelength is by a laparoscopic instrument. In some embodiments, the dye is a dye which fluoresces when exposed to near infrared light. In some embodiments, the dye is a tricarbocyanine dye or an analog thereof. In some embodiments, the tricarbocyanine dye is indocyanine green. In some embodiments, the subject is a human. In some embodiments, the dye is injected between about 10 minutes and 12 hours before the surgical operation. In some embodiments, the dye is injected between about 1 hour and about 6 hours before the surgical operation. In some embodiments, the dye is injected between about 1 hour and about 2 hours before the surgical operation. In some embodiments, the steps of exposing the lymph node to illumination comprising the excitation wavelength, thereby causing the fluorescent dye to fluoresce; and detecting the fluorescence of the dye, thereby localizing the lymph node, are performed during the surgical operation. In some embodiments, the surgical operation is a laparoscopic operation.
-
FIG. 1 .FIG. 1 shows detection of inguinal lymph nodes by near infrared fluorescence (NIRF) through the body wall of a rat in which indocyanine green had been injected into the cavernous bodies of the penis. Arrows indicate the lymphatics and the lymph nodes. -
FIG. 2 .FIG. 2 shows an intraoperative image of inguinal lymph nodes first detected by near infrared fluorescence (NIRF) through the body wall of a rat in which indocyanine green had been injected into the cavernous bodies of the penis. Arrows indicate the lymphatics and the lymph nodes. - Lymph nodes that receive the lymph from a particular organ or region of the body are considered to “drain” that organ or region. As set forth in the Background, various techniques and agents have been used to try to detect the lymph nodes draining penile cancers. Unfortunately, all suffer from various problems, such as exposing the patient to radioactivity, and none have emerged as a standard of care.
- It will be appreciated that penile tumors can spread in two planes: both laterally along the surface of the penis and vertically, into the penis. Thus, a tumor can be considered to have both edges, defining the lateral borders of the tumor, and a base, defining the depth to which the tumor has invaded into the tissue and structures of the penis. Surprisingly, it has now been discovered that the lymph nodes draining the cancer can be localized and visualized by injecting the edges or base of the tumor, or preferably, both, with a non-toxic, fluorescent dye. Thus, if the tumor is located on the glans of the penis, the injections will be in the glans, while a tumor in the prepuce (more familiarly known as the foreskin), the injections will be into the prepuce. For tumors that have invaded into one or both of the corpus cavernosum, injections are made into the base of the tumor in the affected corpus cavernosum. (As persons of skill are aware, “corpus cavernosum” is the singular form and “corpora cavernosa” is the plural form. For convenience, the corpora cavernosa will sometimes be referred to herein as the “cavernous bodies.” Also for convenience of reference, the ability to locate and visualize nodes can be referred to as “localizing” the nodes.)
- The dye injections are typically about 30 to 300 μl each, more preferably about 50 to about 200 μl, still more preferably about 60 to about 175 μl, more preferably about 75 to about 150 μl, more preferably about 90 to about 125 μl each, more preferably about 100 μl, and most preferably 100 μl each, with “about” in this context meaning plus or minus 15 μl. For a small tumor, as few as two shots around the edges or base of the tumor will be sufficient. Larger tumors will typically take 5 shots dispersed around the edges and base. Larger tumors with deeper invasion into the tissues and cavernous bodies could require up to 10 injections. Urologic surgeons are considered to be familiar with the criteria for staging penile cancers, which are based in part on the extent to which the tumor has invaded the tissue; selecting a suitable number of injections for tumors of different sizes is considered to be within the skill of the practitioner.
- In studies in an animal model, injection of an exemplar fluorescent dye, indocyanine green (ICG) resulted in the ability to visualize the lymph nodes in as little as 10 minutes after injection. Thus, if desired, dye injections can be made as soon as the patient is in the operating room and under anesthesia. To minimize the duration of use of the operating room and surgical team, however, the injections will more typically be given pre-operatively. Patients are, typically prepared for penile cancer surgery in a pre-anesthesia room an hour or two before the surgery, during which time they are given mild sedation or a calming medication. Conveniently, the dye injections are made after the sedative has taken effect to reduce the patient's discomfort at receiving small penile injections.
- In animal studies, lymph nodes could be seen through the body wall for days after injection; however, in the context of detecting and visualizing sentinel nodes, periods as long as 24 hours may permit the dye to disperse to more distal lymph nodes. Thus, to facilitate identifying the sentinel nodes rather than more distal lymph nodes to which the dye may disperse, it is preferable to administer the dye 12 hours or less before the surgical operation, with 11, 10, 9, 8, 7, 6, 5, 4, 3, and 2 hours being successively more preferred. In still more preferred embodiments, the dye is administered about 1 to 2 hours before the operation, with “about” in this context meaning one-half hour on either side of the designated time. Most preferably, the dye is injected about 1 hour before the operation, with “about” in this context meaning plus or minus 15 minutes, permitting the dye to reach the sentinel nodes while minimizing the dispersion to more distal nodes.
-
FIG. 1 shows fluorescence in a rat injected in the cavernous bodies with ICG. Arrows point to the lymphatic channels and to the lymph nodes. More than one sentinel nodes were visualized in two rats. No fluorescence was seen in control animals injected with saline. Intraoperative observations confirmed the preoperative localization of the inguinal nodes. All lymph nodes were confirmed by conventional histological review.FIG. 2 shows an intraoperative image of left inguinal lymph nodes following injection of ICG into the cavernous bodies. - It is understood that fluorescent dyes have a particular excitation wavelength which causes the dye to fluoresce and emit light of a particular emission wavelength. As persons of skill are aware, there is a considerable literature on the characteristics of different dyes, including their excitation wavelength and emission wavelength.
- The methods described herein are suitable for use in mammals. Examples of mammals for which the techniques can be used include, but are not limited to, non-human primates, dogs, cats, sheep, cows, pigs, horses, and rabbits. The methods are particularly useful in visualizing lymph nodes in humans, and particularly the lymph nodes draining the penis in humans.
- It is assumed that urologic surgeons and other persons of skill are well familiar with the anatomy of the penis, the prostate, and the surrounding areas, and that no detailed discussion is needed here. For purposes of the present discussion, it is noted that the penis can be thought of as comprising three cylinders. Two, the corpora cavernosa, are disposed on either side of the penis, and make up the bulk of the penis. The third, the corpus spongiosum, which contains the urethra, is disposed in the middle of the penis, in a cleft between the undersides of the corpora cavemosa. A “deep artery” runs down the center of each corpus cavernosum and provides blood to sinusoidal spaces in the respective corpus. The end of the penis distal to the body ends in the glans penis which, in uncircumcised males, is protected by the prepuce.
- As noted in the Background, the National Cancer Institute (NCI) indicates that, when diagnosed early (stage 0, stage I, and stage II), penile cancer is highly curable, but curability decreases sharply for stage III and stage 1V. Criteria for staging penile cancer are known in the art. The most common system is the “TNM” (for: “tumor, node, metastasis”) system of the American Joint Committee on Cancer, set forth at, e.g., Penis: American Joint Committee on Cancer, AJCC Cancer Staging Manual, 6th Ed., Springer, NY N.Y., 2002, pp. 302-8. The NCI website notes with regard to stage 0 cancer, that carcinoma in situ of the penis is referred to as erythroplasia of Queyrat when it occurs on the glans, and Bowen's disease when it occurs on the penile shaft. These precursor lesions progress to invasive squamous cell carcinoma in 5% to 15% of cases. The NCI website notes that surgical excision can result in scarring, deformity, and impaired function, and that Mohs micrographic surgery, which involves the excision of successive horizontal layers of tissue with microscopic examination of each layer in frozen section, has been developed for use in patients with in situ and invasive penile cancers. See, e.g., Mohs et al., J. Urol. 133(6): 961-6 (1985).
- With regard to therapeutic options for stage 1 penile cancer, the NCI website states that, for lesions limited to the foreskin, wide local excision with circumcision may be adequate therapy for control. For infiltrating tumors of the glans, with or without involvement of the adjacent skin, it states that the choice of therapy is dictated by tumor size, extent of infiltration, and degree of tumor destruction of normal tissue. It further states that equivalent therapeutic options include: penile amputation, radiation therapy (i.e., external-beam radiation therapy and brachytherapy), and microscopically controlled surgery. It indicates that, because of the high incidence of microscopic node metastases, elective adjunctive inguinal dissection of clinically uninvolved (negative) lymph nodes in conjunction with amputation is often used for patients with poorly differentiated tumors. Lymphadenectomy, however, can carry substantial morbidity, such as infection, skin necrosis, wound breakdown, chronic edema, and a low, but finite, mortality rate. The NCI indicates that the impact of prophylactic lymphadenectomy on survival is not known.
- The NCI states that stage II penile cancer is most frequently managed by penile amputation for local control. Whether the amputation is partial, total, or radical will depend on the extent and location of the neoplasm. External beam radiation therapy and brachytherapy with surgical salvage are alternative approaches.
- The NCI site further states that inguinal adenopathy in patients with stage III penile cancer is common but may be the result of infection rather than neoplasm. The website further states that, if palpable enlarged lymph nodes exist 3 or more weeks after removal of the infected primary lesion and completion of a course of antibiotic therapy, bilateral inguinal lymph node dissection should be performed. The methods of the present invention can be performed to assist in dissection of the nodes. Since, in this case, the primary lesion has been removed, the injections are of course made into the cavernous bodies. In cases of proven regional inguinal lymph node metastasis without evidence of distant spread, bilateral ilioinguinal dissection is the treatment of choice. Clinically evident regional lymph node metastasis without evidence of distant spread is an indication for bilateral ilioinguinal lymph node dissection after penile amputation. Radiation therapy may be considered as an alternative to lymph node dissection in patients who are not surgical candidates. Postoperative radiation therapy may decrease incidence of inguinal recurrences.
- With respect to stage 1V disease, the NCI notes that there is no curative standard treatment. Therapy is directed at palliation, which may be achieved either with surgery or radiation therapy. The standard treatment options include palliative surgery for control of the local penile lesion and palliative radiation therapy for the primary tumor, regional adenopathy, and bone metastases.
- Conveniently, the device used for visualization comprises both a laser and a camera. For convenience of reference, the discussion below refers to the exemplar dye ICG. Persons of skill will recognize that the other dyes mentioned herein as suitable for use in the inventive methods and procedures could be substituted for ICG, with the light source selected or adjusted to provide illumination optimized for the excitation frequency suitable for the particular dye chosen and the device for capturing the light emitted by the dye being selected or adjusted to be able to receive light of the appropriate frequency. For use with ICG, the laser conveniently consists of a laser diode providing a maximum of 3 W output at 806 nm. For other dyes, the laser diode is selected to provide a light with a wavelength at an excitation frequency appropriate for the dye selected.
- The laser output is decollimated (i.e. optics are used to spread out the laser light from a tight beam) to provide even illumination over a field of view, for example, 7.6 cm by 7.6 cm at a working distance of 30 cm. The imaging system typically has a camera containing a charge-coupled device (“CCD”) or a complementary symmetry metal oxide semiconductor (“CMOS”) image sensor sensitive into the near infrared spectrum and, for use with ICG, is equipped with an 815 nm edge filter. In some embodiments, the laser or camera or both, are supported by an articulated arm connected to a wheeled base. This allows the imaging head to be moved into close proximity to the surgical table and for vertical movement of the head to attain an appropriate focal distance above the area of interest. The imaging head and extension arm that protrudes over the surgical field are typically covered with an optically transparent sterile drape. The laser can conveniently be activated by means of a computer command or by foot pedal. Laser/camera devices suitable for intra-operative imaging are commercially available. In some preferred embodiments, the laser/camera device is a SPY® Intra-operative Imaging System, a HELIOS® Imaging System, or a LUNA® Imaging System (all by Novadaq Technologies, Inc., Mississauga, Ontario, Canada).
- In some embodiments, an instrument having an optical configuration similar to a fluorescence microscope may be used, in which a dichroic mirror is used to split the paths of the illumination (the excitation light). The excitation light reflects off the surface of the dichroic mirror into the objective, while the fluorescence emission passes through the dichroic mirror to the eyepiece or is converted into a signal to be presented on a screen. The instrument may further have an excitation filter or an emission filter, or both, to select the wavelengths appropriate for each function. Conveniently, the filters are interference filters, which block transmission of frequencies out of their bandpass.
- For visualizing the lymph nodes and channels in the area of interest, the ICG is administered by injection into the cavernous bodies, preferably into the crura, permitting the dye to be transported through the lymphatic channels serving the area to the sentinel node or nodes. Following an interval sufficient for the dye to be transported through the channels to the nodes, a 806 nm excitation light causes the dye to fluoresce, emitting light at 830 nm. The emitted light can then be imaged directly or, preferably, is captured using an imaging system. As noted, the capture system is typically a video camera containing a CCD or CMOS image sensor. The capture system feeds the image to a monitor so that the surgeon can visualize the fluorescence of the dye in the lymph nodes in the area of interest in real time. Filters limit the light detected to a range appropriate for the selected fluorescence wavelengths. Optionally, the camera is also attached to a computer and the image is saved, which not only permits documentation of the extent to which the tumor or tumors, but also can be used for training urologic surgeons, nurses, and other medical staff. Typically, the time required for positioning the device is 2 minutes, while the total time that the vessels are illuminated with laser light is 30 seconds.
- The methods described herein are suitable for use in mammals. Examples of suitable mammals include, but are not limited to, humans, non-human primates, dogs, cats, sheep, cows, pigs, horses, mice, rats, rabbits, and guinea pigs. Use in humans is primates, and particularly in humans, is preferred.
- As persons of skill are aware, fluorescent dyes have a particular excitation wavelength which causes the dye to fluoresce and emit light of a particular emission wavelength. Persons of skill will appreciate that a considerable literature is available in the art on the characteristics of different dyes, including their excitation wavelength and emission wavelength. This literature is well known, and will not be set forth in detail herein.
- The dye is imaged by exciting it with a light that has an excitation wavelength appropriate for the particular dye used. Persons of skill are aware that a variety of dyes exist, and that each dye has an excitation wavelength and an emission wavelength. Some dyes, for example, fluoresce under ultraviolet (“UC”) illumination while others fluoresce under incandescent illumination. The literature on the use of fluorescent dyes and probes in biological assays includes, for example, Dewey, T. G., Ed., Biophysical and Biochemical Aspects of Fluorescence Spectroscopy, Plenum Publishing (1991), Guilbault, G. G., Ed., Practical Fluorescence, Second Edition, Marcel Dekker (1990), Lakowicz, J. R., Ed., Topics in Fluorescence Spectroscopy: Techniques (Volume 1, 1991); Principles (Volume 2, 1991); Biochemical Applications (Volume 3, 1992); Probe Design and Chemical Sensing (Volume 4, 1994); Nonlinear and Two-Photon Induced Fluorescence (Volume 5, 1997); Protein Fluorescence (Volume 6, 2000); DNA Technology (Volume 7, 2003); Plenum Publishing, and Lakowicz, J. R., Principles of Fluorescence Spectroscopy, Second Edition, Plenum Publishing (1999) and W. T. Mason, ed., Fluorescent and Luminescent Probes for Biological Activity. A Practical Guide to Technology for Quantitative Real-Time Analysis, Academic Press (Second Ed., 1999).
- Preferably, the dye selected is one that has low toxicity and has excitation and emission peaks within the “optical window” of tissue, where absorption due to endogenous chromophores is low. Preferred fluorescent dyes suitable for use in the methods of the invention are non-toxic dyes which fluoresce when exposed to radiant energy, e.g. light. Preferably, the dyes are near infrared fluorochromes, or “NIRF” that emit light in the near infra red spectrum. Near infrared light can penetrate tissue to a depth of several millimeters to a few centimeters. In some embodiments, the dye is a tricarbocyanine dye, and in particularly preferred embodiments, is ICG. In other embodiments the dye is selected from fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, fluorescamine, Rose Bengal, trypan blue, and fluoro-gold. The dyes may be mixed or combined. In some embodiments, dye analogs may be used. A “dye analog” is a dye that has been chemically modified, but still retains its ability to fluoresce when exposed to radiant energy of an appropriate wavelength.
- ICG, Fast Blue and Fluorogold have all been used in mammals with low evidence of toxicity and are preferred. As noted, ICG is particularly preferred both because it has low toxicity and because it has been approved by the Food and Drug Administration for several diagnostic purposes in humans. Further, its absorption (excitation) and emission peaks (805 and 835 nm, respectively) lie within the “optical window” of tissue. ICG is commercially available from, for example, Akorn, Inc. (Buffalo Grove, Ill.), which sells it under the name IC-GREEN™. After intravenous injection, ICG is bound within 1 to 2 seconds, mainly to globulins (1-lipoproteins), and remains intravascular, with normal vascular permeability. ICG is not metabolized in the body and is excreted exclusively by the liver, with a plasma half-life of 3 to 4 minutes. It is not reabsorbed from the intestine and does not undergo enterohepatic recirculation. The recommended dose for ICG video angiography is 0.2 to 0.5 mg/kg; the maximum daily dose should not exceed 5 mg/kg.
- For intraoperatively visualizing the lymph nodes and channels, the surgical field, or the portion of the surgical field in which imaging is desired, is illuminated with a light of the excitation wavelength or wavelengths suitable for the dye or dyes used. Since the channels are thin and the nodes are small (accounting in part for the difficulty in discerning them with the unaided eye), ambient light may need to be dimmed to permit the fluorescence to be seen. Observation will typically also require magnification. Where the excitation wavelength is outside of the visible range (where, for example, the excitation wavelength is in the ultraviolet or near infrared range), the light source may be designed to permit switching or “toggling” between the excitation wavelength and visible light. This permits the practitioner to note the position of the node or nodes using the fluorescent property in relation to the rest of the surgical field and surrounding (but non-fluorescent) structures.
- In some embodiments, an instrument having an optical configuration similar to a fluorescence microscope may be used, in which a dichroic mirror is used to split the paths of the illumination (the excitation light). The excitation light reflects off the surface of the dichroic mirror into the objective, while the fluorescence emission passes through the dichroic mirror to the eyepiece or is converted into a signal to be presented on a screen. The instrument may further have an excitation filter or an emission filter, or both, to select the wavelengths appropriate for each function. Conveniently, the filters are interference filters, which block transmission of frequencies out of their bandpass.
- The dye is typically administered by an injection into one or both of the corpora cavernosa. Typically, the dye will be administered some hours preoperatively, to permit the dye to be transported to the nodes in the area of interest prior to commencing the surgical operation.
- Conveniently, the dye may be administered in the patient's room. Typically, the dye is administered sufficiently before the intended surgery to permit the dye to flow to the sentinel nodes draining the tumor area, but not so long before the surgery that the dye has been cleared from the nodes. Since the nodes could be detected through the body wall of the animals from 2 hours to 7 days after injection, it appears that the dye can be administered at the convenience of the patient and the practitioner from 2 hours up to a week before the intended surgery. Typically, however, a patient presenting with penile cancer will be injected with the dye no more than a few days before surgery is contemplated, since delay in performing the surgery will rarely be to the patient's benefit. Typically, therefore, the dye is administered at least about 2 hours but not more than 72 hours before the intended surgery. In some embodiments, the dye is administered at least about 2 hours but not more than 48 hours before the intended surgery. In other embodiments, the dye is administered at least about 2 hours but not more than 36 hours before the intended surgery. In preferred embodiments, the dye is administered between about 2 hours to 24 hours before the intended surgery. In still preferred embodiments, the dye is administered between about 2 hours to about 14 hours before the intended surgery, with “about” meaning a half hour on either side. Whether the patient has been injected too recently to provide adequate time for the dye to drain to the lymph nodes (for example, a half hour after injection, the dye would not yet be expected to have drained sufficiently to the nodes for optimal detection) can be readily determined pre-operatively by simply illuminating the groin with near infrared illumination under conditions permitting detecting any light emitted by the dye. If fluorescence is not sufficient to permit visualization of the nodes in the groin, a technician can simply reilluminate the area at half hour intervals or such other intervals as may be convenient until sufficient dye has drained to the sentinel lymph nodes to permit ready visualization.
- The maximum daily dosage of ICG for adults is 2 mg/kg. There is no data available describing the signs, symptoms, or laboratory findings accompanying an overdose of ICG. The LD50 after IV administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats, and 50 to 80 mg/kg in rabbits.
- Intraoperative video angiography is performed with a laser-fluorescence imaging device (Novadaq Technologies, Inc., Mississauga, Ontario, Canada) consisting of a near infrared (NIR) laser light source and a NIR-sensitive digital camcorder. For measurements, the unit is positioned 30 to 40 cm from the area of interest. ICG, dissolved in water, is then injected as a bolus. The NIR light emitted by the laser light source induces ICG fluorescence. The fluorescence is recorded by a digital video camera, with optical filtering to block ambient and laser light so that, when desired, only ICG fluorescence is captured. Images can be observed on screen in real time (25-30 images/sec). The images can be reviewed and stored on the digital video camera or transferred to a computer or to storage media.
- Sprague-Dawley rats, 60 to 100 days old, weighing 275-325 grams are used. All animals are anesthetized using intraperitoneal injection of Ketamine/Xylazine (40-80 mg/kg and 5/10 mg/kg, respectively) or isoflurane. No pre-anesthetic medications are used. When appropriate depth of anesthesia is reached, positioning of the animal takes place. All animals are fastened to a padded and heated restraint device in the supine position using gauze knots to fix all four extremities. Depth of anesthesia, regularity of respirations, and heart beat palpation are repeatedly checked. A pulse oximeter may be used to monitor the animal. Placebo (distilled water) or fluorochromes, ICG or Fluorogold, is administered by intra-penile, sub-albugineal injection of 25 ul of ICG diluted in 100 μl of water for injection, per cavernous body.
- Surgery/Procedure starts after appropriate preparation of surgical field by Povidone-Iodine scrub, 70% Isopropyl Alcohol and Povidone-Iodine solution. The surgical field includes the genital area, lower abdomen and perineum. The penis is squeezed out from the prepuce, then stretched using finger grip of the glans until maximally stretched; a clamp used for atraumatic clamping in neurosurgical operation on brain aneurysms is then placed at the root of the penis. This allows blood to pool inside the cavernous bodies, producing an erection and permitting easier application of a 27 Gauge butterfly needle to both sub-albugineal spaces. Adequate placement is assured when blood is easily aspirated. 0.5 mg/kg of ICG and 1 mg/kg of Fluorogold diluted in distilled water to total volume of 50 μl is injected, 25 μl per cavernous body. A placebo group is injected using 25 μl of distilled water per cavernous body. Animals in all groups have an exploratory laparotomy through midline lower incision, with intraoperative identification of nodes draining the penis. Midline incisions are made from umbilicus to pubis. Bowels and testicles after their release from scrotal attachments are packed back to upper abdomen. For better visualization of the pelvic structures, surgical loupes with 3.8× magnification are used. After release of the clamps, the 27 Gauge needles are removed, but slight finger pressure at the injection sites is maintained for 3-5 minutes to prevent extravasation. Buprenorphine (0.01-0.05 mg/kg) is administered intraoperatively and then as needed to control pain.
- Post-procedurally, optimal recovery is routinely performed in all animals: animals are kept warm using warming packs, pads and lamps, the animals are placed on a paper towel, and are rotated from side to side every 15 minutes until they are able to maintain sternal recumbence. 3-4 ml of Lactated Ringer solution, warmed to 37° C., is administered subcutaneously and unilaterally in the flank region, preventing postoperative dehydration of the animal. Animals are attended at all times during postoperative recovery. The animals are then returned to their home cages, and hydration is assessed on a daily basis. Analgesia is used for all animals for postoperative pain. Animals are checked for signs of pain every 6 hours during first 24 hours post-surgery and then every 12 hours until euthanasia. Signs of acute pain are guarding (protecting the painful area), vocalization, especially when the animal moves or the painful area is touched, licking, biting, scratching or shaking a particular area, pacing, lack of mobility as seen with joint, colic or gut pain or an unusual gait posture during movement, failure to groom, causing an unkempt appearance, abnormal resting postures, loss of appetite or reduction in water consumption, and changes in behavior or signs of aggression.
- To perform harvesting of lymph nodes, the rats undergo a second surgery (non-survival) and postmortem harvesting at chosen timepoints after fluorochrome injection.
- Anesthesia identical to the first procedure is administered and then appropriate skin preparation for surgery is performed. The same level of incision is used in second surgery/harvesting procedure. The bladder and prostate are exposed as in the first surgery. The penis is denuded of skin and the prepuce circumcised. The animal is euthanized by cardiac exsanguination. Death of the animal is confirmed using pulse oximeter and observation of complete absence of heart contractions.
- Twenty two 22 male Sprague-Dawley rats received penile intracavernous ICG injections (20 μl of 0.25 mg/ml). From 2 hours to 7 days later, near infrared fluorescence (NIRF) imaging was performed both before and during dissection. Control rats received comparable saline injections at several time points. A Novadaq intraoperative NIRF imaging system (SPY®) was used for macroscopic fluorescence imaging and an Olympus NIRF microscope IX 70 (Olympus America, Inc., Center Valley, Pa.) was used for histology. All animals were anesthetized and shaved before imaging. All visualized nodes were sent for NIR microscopy and haematoxylin and eosin (H&E) staining for histological examination.
- Inguinal lymph node NIRF was detected through the body wall from 2 hours to 7 days after ICG injection (
FIG. 1 ). More than one pair of sentinel lymph nodes were visualized in 2 rats. No fluorescence was seen in controls. Intraoperative observations confirmed preoperative localization of all inguinal nodes (FIG. 2 ). Inguinal and iliac sentinel lymph nodes were clearly visualized with NIRF, and were difficult to visualize otherwise. Lymphatic channels were seen leading to sentinel lymph nodes at 6, 12 and 24 hours (FIG. 1 ). Lymphatic channels leading to the sentinel lymph nodes were seen in animals examined at 6, 12, and 24 hours post-injection of ICG. (FIG. 1 ). All lymph nodes were confirmed by NIR microscopy and by conventional histology. Thus, NIR fluorescence using ICG facilitates both pre- and intraoperative identification of the first site of penile lymphatic drainage. The methods of the invention should therefore improve the accuracy of surgical staging in patients with penile carcinomas. - It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8825140B2 (en) | 2001-05-17 | 2014-09-02 | Xenogen Corporation | Imaging system |
US20140267603A1 (en) * | 2013-03-15 | 2014-09-18 | Intuitive Surgical Operations, Inc. | Depth based modification of captured images |
US9433350B2 (en) | 2009-06-10 | 2016-09-06 | W.O.M. World Of Medicine Gmbh | Imaging system and method for the fluorescence-optical visualization of an object |
US9610021B2 (en) | 2008-01-25 | 2017-04-04 | Novadaq Technologies Inc. | Method for evaluating blush in myocardial tissue |
US9816930B2 (en) | 2014-09-29 | 2017-11-14 | Novadaq Technologies Inc. | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
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US10434190B2 (en) | 2006-09-07 | 2019-10-08 | Novadaq Technologies ULC | Pre-and-intra-operative localization of penile sentinel nodes |
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US10631746B2 (en) | 2014-10-09 | 2020-04-28 | Novadaq Technologies ULC | Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography |
US10992848B2 (en) | 2017-02-10 | 2021-04-27 | Novadaq Technologies ULC | Open-field handheld fluorescence imaging systems and methods |
Citations (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5149671A (en) * | 1990-12-03 | 1992-09-22 | Grumman Aerospace Corporation | Method for forming multilayer indium bump contact |
US5279298A (en) * | 1992-11-20 | 1994-01-18 | The Johns Hopkins University | Method and apparatus to identify and treat neovascular membranes in the eye |
US5438989A (en) * | 1990-08-10 | 1995-08-08 | Hochman; Darryl | Solid tumor, cortical function, and nerve tissue imaging methods and device |
US5465718A (en) * | 1990-08-10 | 1995-11-14 | Hochman; Daryl | Solid tumor, cortical function, and nerve tissue imaging methods and device |
US5496369A (en) * | 1994-02-09 | 1996-03-05 | University Of Iowa Research Foundation | Human cerebral cortex neural prosthetic |
US5519534A (en) * | 1994-05-25 | 1996-05-21 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Irradiance attachment for an optical fiber to provide a uniform level of illumination across a plane |
US5699798A (en) * | 1990-08-10 | 1997-12-23 | University Of Washington | Method for optically imaging solid tumor tissue |
US6196226B1 (en) * | 1990-08-10 | 2001-03-06 | University Of Washington | Methods and apparatus for optically imaging neuronal tissue and activity |
US6331703B1 (en) * | 1999-03-12 | 2001-12-18 | Ethicon Endo-Surgery, Inc. | Guidance method for radiation detection |
US6335429B1 (en) * | 1997-10-10 | 2002-01-01 | Cytovia, Inc. | Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof |
US6351663B1 (en) * | 1999-09-10 | 2002-02-26 | Akorn, Inc. | Methods for diagnosing and treating conditions associated with abnormal vasculature using fluorescent dye angiography and dye-enhanced photocoagulation |
US20020146369A1 (en) * | 1992-05-06 | 2002-10-10 | Immunomedics, Inc. | Intraoperative, intravascular and endoscopic tumor and lesion detection, biopsy and therapy |
US6485413B1 (en) * | 1991-04-29 | 2002-11-26 | The General Hospital Corporation | Methods and apparatus for forward-directed optical scanning instruments |
US20030156252A1 (en) * | 2001-10-19 | 2003-08-21 | Morris Robert E. | Macula cover and method |
US20030187349A1 (en) * | 2002-03-29 | 2003-10-02 | Olympus Optical Co., Ltd. | Sentinel lymph node detecting method |
US20030232016A1 (en) * | 2002-04-17 | 2003-12-18 | Russell Heinrich | Nerve identification and sparing method |
US20030236458A1 (en) * | 1999-08-03 | 2003-12-25 | Biophysica Llc | Spectroscopic systems and methods for detecting tissue properties |
US6671540B1 (en) * | 1990-08-10 | 2003-12-30 | Daryl W. Hochman | Methods and systems for detecting abnormal tissue using spectroscopic techniques |
US20040109231A1 (en) * | 2002-08-28 | 2004-06-10 | Carl-Zeiss-Stiftung Trading As Carl Zeiss | Microscopy system, microscopy method and a method of treating an aneurysm |
US20040156782A1 (en) * | 2003-02-12 | 2004-08-12 | Akorn, Inc. | Methods of using indocyanine green (ICG) dye |
US20040171827A1 (en) * | 2002-10-25 | 2004-09-02 | Li-Cor, Inc. | Phthalocyanine dyes |
US20040174495A1 (en) * | 2001-06-05 | 2004-09-09 | Adaptive Optics Associates, Inc. | Method of and system for examining the human eye with a wavefront sensor-based ophthalmic instrument |
US6804549B2 (en) * | 2000-04-25 | 2004-10-12 | Fuji Photo Film Co., Ltd. | Sentinel lymph node detection method and system therefor |
US20040206364A1 (en) * | 2002-07-17 | 2004-10-21 | Robert Flower | Combined photocoagulation and photodynamic therapy |
US6821946B2 (en) * | 2000-05-10 | 2004-11-23 | University College London | Repair of nerve damage |
US6853857B2 (en) * | 2001-05-01 | 2005-02-08 | Pulsion Medical Systems Ag | Method, device and computer program for determining the blood flow in a tissue or organ region |
US20050069525A1 (en) * | 2001-11-16 | 2005-03-31 | Wiberg Mikael | Nerve repair unit and method of producing it |
US20050107380A1 (en) * | 2000-01-18 | 2005-05-19 | Nimmo Alan J. | Brain, spinal and nerve injury treatment |
US6899675B2 (en) * | 2002-01-15 | 2005-05-31 | Xillix Technologies Corp. | Fluorescence endoscopy video systems with no moving parts in the camera |
US6915154B1 (en) * | 1999-09-24 | 2005-07-05 | National Research Council Of Canada | Method and apparatus for performing intra-operative angiography |
US20050182321A1 (en) * | 2002-03-12 | 2005-08-18 | Beth Israel Deaconess Medical Center | Medical imaging systems |
US20050197583A1 (en) * | 1998-02-11 | 2005-09-08 | Britton Chance | Detection, imaging and characterization of breast tumors |
US20060013768A1 (en) * | 2004-07-13 | 2006-01-19 | Woltering Eugene A | Injection of a radioactive dye for sentinel lymph node identification |
US20060108509A1 (en) * | 2004-09-09 | 2006-05-25 | Frangioni John V | Systems and methods for multi-modal imaging |
US20060241499A1 (en) * | 2005-02-24 | 2006-10-26 | Irion Klaus M | Multifunctional fluorescence diagnosis system |
US20070203413A1 (en) * | 2003-09-15 | 2007-08-30 | Beth Israel Deaconess Medical Center | Medical Imaging Systems |
Family Cites Families (314)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4109647A (en) | 1977-03-16 | 1978-08-29 | The United States Of America As Represented By The Secretary Of The Department Of Health, Education And Welfare | Method of and apparatus for measurement of blood flow using coherent light |
US4263916A (en) | 1978-03-27 | 1981-04-28 | University Of Southern California | Image averaging for angiography by registration and combination of serial images |
US4162405A (en) | 1978-05-23 | 1979-07-24 | Britton Chance | Flying spot fluoro-meter for oxidized flavoprotein and reduced pyridine nucleotide |
US4200801A (en) | 1979-03-28 | 1980-04-29 | The United States Of America As Represented By The United States Department Of Energy | Portable spotter for fluorescent contaminants on surfaces |
US4394199A (en) | 1981-09-08 | 1983-07-19 | Agnus Chemical Company | Explosive emulsion composition |
JPS58141135A (en) | 1981-10-20 | 1983-08-22 | 富士写真フイルム株式会社 | Image transmitting system of endoscope using solid image sensor |
EP0091805B1 (en) | 1982-04-08 | 1989-07-26 | Olympus Optical Co., Ltd. | Endoscope focus state detectors |
JPS58222331A (en) | 1982-06-21 | 1983-12-24 | Sony Corp | Reproducer of character information |
JPS5940830A (en) | 1982-08-31 | 1984-03-06 | 浜松ホトニクス株式会社 | Apparatus for diagnosis of cancer using laser beam pulse |
JPS5969721A (en) | 1982-10-15 | 1984-04-20 | Olympus Optical Co Ltd | Endoscope measuring device |
JPS5970903A (en) | 1982-10-15 | 1984-04-21 | Olympus Optical Co Ltd | Automatic measuring apparatus of endoscope |
US4541438A (en) | 1983-06-02 | 1985-09-17 | The Johns Hopkins University | Localization of cancerous tissue by monitoring infrared fluorescence emitted by intravenously injected porphyrin tumor-specific markers excited by long wavelength light |
US4532918A (en) | 1983-10-07 | 1985-08-06 | Welch Allyn Inc. | Endoscope signal level control |
JPS60256443A (en) | 1984-05-31 | 1985-12-18 | オムロン株式会社 | Image measuring apparatus |
US4559557A (en) | 1984-06-01 | 1985-12-17 | General Electric Company | Region-of-interest digital subtraction angiography |
SE455646B (en) | 1984-10-22 | 1988-07-25 | Radians Innova Ab | FLUORESCENT DEVICE |
US5318024A (en) | 1985-03-22 | 1994-06-07 | Massachusetts Institute Of Technology | Laser endoscope for spectroscopic imaging |
US4718417A (en) | 1985-03-22 | 1988-01-12 | Massachusetts Institute Of Technology | Visible fluorescence spectral diagnostic for laser angiosurgery |
US5125404A (en) | 1985-03-22 | 1992-06-30 | Massachusetts Institute Of Technology | Apparatus and method for obtaining spectrally resolved spatial images of tissue |
DE3511255A1 (en) | 1985-03-28 | 1986-10-02 | Grün Optik Wetzlar GmbH, 6330 Wetzlar | ARRANGEMENT FOR THE INDIVIDUAL CONTROL OF THE INTENSITY OF SEVERAL SPECTRAL LAMPS |
CN85100424B (en) | 1985-04-01 | 1986-10-29 | 上海医疗器械研究所 | Inherent fluorescence diagnostic instrument for malignant tumor |
US4619249A (en) | 1985-07-24 | 1986-10-28 | Kim Landry | Transcutaneous intravenous illuminator |
AT387860B (en) | 1985-09-16 | 1989-03-28 | Optical Sensing Technology | METHOD AND DEVICE FOR TUMOR DIAGNOSIS BY MEANS OF SERA |
US4719508A (en) | 1985-10-02 | 1988-01-12 | Olympus Optical Co., Ltd. | Endoscopic photographing apparatus |
US5134662A (en) | 1985-11-04 | 1992-07-28 | Cell Analysis Systems, Inc. | Dual color camera microscope and methodology for cell staining and analysis |
US5042494A (en) | 1985-11-13 | 1991-08-27 | Alfano Robert R | Method and apparatus for detecting cancerous tissue using luminescence excitation spectra |
US4930516B1 (en) | 1985-11-13 | 1998-08-04 | Laser Diagnostic Instr Inc | Method for detecting cancerous tissue using visible native luminescence |
US4774568A (en) | 1986-01-27 | 1988-09-27 | Kabushiki Kaisha Toshiba | Endoscopic apparatus |
JPS62247232A (en) | 1986-04-21 | 1987-10-28 | Agency Of Ind Science & Technol | Fluorescence measuring apparatus |
GB2203831B (en) | 1986-07-07 | 1991-02-06 | Academy Of Applied Sciences | Apparatus and method for the diagnosis of malignant tumours |
JPH0763443B2 (en) | 1986-09-30 | 1995-07-12 | 株式会社東芝 | Electronic endoscope |
JPS63122421A (en) | 1986-11-12 | 1988-05-26 | 株式会社東芝 | Endoscope apparatus |
US5255087A (en) | 1986-11-29 | 1993-10-19 | Olympus Optical Co., Ltd. | Imaging apparatus and endoscope apparatus using the same |
JP2572394B2 (en) | 1987-03-19 | 1997-01-16 | オリンパス光学工業株式会社 | Electronic endoscope |
JPH0783B2 (en) | 1987-03-30 | 1995-01-11 | 株式会社東芝 | Electronic endoscopic device |
US4986262A (en) | 1987-03-31 | 1991-01-22 | Kabushiki Kaisha Toshiba | Measuring endoscope |
US4852579A (en) | 1987-04-20 | 1989-08-01 | Karl Storz Endoscopy Gmbh And Company | Photocharacterization and treatment of normal abnormal and ectopic endometrium |
US4900934A (en) | 1987-07-15 | 1990-02-13 | University Of Utah | Apparatus for simultaneous visualization and measurement of fluorescence from fluorescent dye-treated cell preparations and solutions |
JPH0824668B2 (en) | 1987-09-14 | 1996-03-13 | オリンパス光学工業株式会社 | Electronic endoscopic device |
US4858001A (en) | 1987-10-08 | 1989-08-15 | High-Tech Medical Instrumentation, Inc. | Modular endoscopic apparatus with image rotation |
JPH01160525A (en) | 1987-12-17 | 1989-06-23 | Olympus Optical Co Ltd | Endoscope |
DE3906860A1 (en) | 1988-03-08 | 1989-09-28 | Fraunhofer Ges Forschung | Device for producing an angiography |
JPH01236879A (en) | 1988-03-17 | 1989-09-21 | Canon Inc | Picture encoder |
JPH06105190B2 (en) | 1988-03-31 | 1994-12-21 | 工業技術院長 | Signal analyzer |
US4998972A (en) | 1988-04-28 | 1991-03-12 | Thomas J. Fogarty | Real time angioscopy imaging system |
US5078150A (en) | 1988-05-02 | 1992-01-07 | Olympus Optical Co., Ltd. | Spectral diagnosing apparatus with endoscope |
IL90188A0 (en) | 1988-05-18 | 1989-12-15 | Cryopharm Corp | Process and medium for the lyophilization of erythrocytes |
US4938205A (en) | 1988-05-27 | 1990-07-03 | The University Of Connecticut | Endoscope with traced raster and elemental photodetectors |
US5178616A (en) | 1988-06-06 | 1993-01-12 | Sumitomo Electric Industries, Ltd. | Method and apparatus for intravascular laser surgery |
US4995396A (en) | 1988-12-08 | 1991-02-26 | Olympus Optical Co., Ltd. | Radioactive ray detecting endoscope |
US5419323A (en) | 1988-12-21 | 1995-05-30 | Massachusetts Institute Of Technology | Method for laser induced fluorescence of tissue |
US5353799A (en) | 1991-01-22 | 1994-10-11 | Non Invasive Technology, Inc. | Examination of subjects using photon migration with high directionality techniques |
JP2987816B2 (en) | 1989-01-30 | 1999-12-06 | オリンパス光学工業株式会社 | Fluorescence observation device |
DE3903019A1 (en) | 1989-02-02 | 1990-08-09 | Hell Rudolf Dr Ing Gmbh | OPTICAL COLOR DIVIDER ARRANGEMENT |
SE8900612D0 (en) | 1989-02-22 | 1989-02-22 | Jonas Johansson | TISSUE CHARACTERIZATION USING A BLOOD-FREE FLUORESCENCE CRITERIA |
EP0466828A1 (en) | 1989-04-14 | 1992-01-22 | Massachusetts Institute Of Technology | Spectral diagnosis of diseased tissue |
US5421337A (en) | 1989-04-14 | 1995-06-06 | Massachusetts Institute Of Technology | Spectral diagnosis of diseased tissue |
KR100190423B1 (en) | 1989-06-06 | 1999-06-01 | 기타지마 요시도시 | Apparatus for repairing defects in emulsion masks by passing laser light through a variable shaped aperture |
US4993404A (en) | 1989-06-26 | 1991-02-19 | Lane Timothy G | Fluoroscopy switching device |
CN1049781A (en) | 1989-09-02 | 1991-03-13 | 住友电气工业株式会社 | The laser surgery equipment that is used for vascular surgery |
JPH0614921B2 (en) | 1989-09-29 | 1994-03-02 | 浜松ホトニクス株式会社 | Fluorescence observation device for biological tissue |
DE69114314T2 (en) | 1990-01-08 | 1996-04-18 | Ernest M D Feiler | Diagnostic procedure for measuring blood flow. |
US5091652A (en) | 1990-01-12 | 1992-02-25 | The Regents Of The University Of California | Laser excited confocal microscope fluorescence scanner and method |
US5420628A (en) | 1990-01-16 | 1995-05-30 | Research Development Foundation | Video densitometer with determination of color composition |
US5131398A (en) | 1990-01-22 | 1992-07-21 | Mediscience Technology Corp. | Method and apparatus for distinguishing cancerous tissue from benign tumor tissue, benign tissue or normal tissue using native fluorescence |
US4995398A (en) | 1990-04-30 | 1991-02-26 | Turnidge Patrick A | Coronary angiography imaging system |
US5071417A (en) | 1990-06-15 | 1991-12-10 | Rare Earth Medical Lasers, Inc. | Laser fusion of biological materials |
US5845639A (en) | 1990-08-10 | 1998-12-08 | Board Of Regents Of The University Of Washington | Optical imaging methods |
US5997844A (en) | 1991-02-08 | 1999-12-07 | Diatide, Inc. | Technetium-99m labeled peptides for imaging |
JPH04297236A (en) | 1991-03-26 | 1992-10-21 | Toshiba Corp | Digital fluorography system |
JPH04307024A (en) | 1991-04-02 | 1992-10-29 | Olympus Optical Co Ltd | Electronic endoscope apparatus |
US5377676A (en) | 1991-04-03 | 1995-01-03 | Cedars-Sinai Medical Center | Method for determining the biodistribution of substances using fluorescence spectroscopy |
US5318023A (en) | 1991-04-03 | 1994-06-07 | Cedars-Sinai Medical Center | Apparatus and method of use for a photosensitizer enhanced fluorescence based biopsy needle |
US5117466A (en) | 1991-04-30 | 1992-05-26 | The United States Of America As Represented By The United States Department Of Energy | Integrated fluorescence analysis system |
CA2042075C (en) | 1991-05-08 | 2001-01-23 | Branko Palcic | Endoscopic imaging system |
US5225883A (en) | 1991-06-05 | 1993-07-06 | The Babcock & Wilcox Company | Video temperature monitor |
SE468925B (en) | 1991-08-22 | 1993-04-19 | Gert Nilsson | A METHOD AND APPARATUS SHOULD REDUCE THE DISTANCE-BASED FACTOR IN Saturation of STRAIGHT MOVEMENTS WITH AN IMAGING LASER-DOUBLE TECHNIQUE, SPECIFICALLY IN SEATING BLOOD PERFUSION THROUGH |
US5377686A (en) | 1991-10-11 | 1995-01-03 | The University Of Connecticut | Apparatus for detecting leakage from vascular tissue |
JP3297725B2 (en) | 1991-12-09 | 2002-07-02 | 国立循環器病センター総長 | Contrast-enhanced blood vessel high-precision pipe diameter measuring device |
US5214503A (en) | 1992-01-31 | 1993-05-25 | The United States Of America As Represented By The Secretary Of The Army | Color night vision camera system |
US5235984A (en) | 1992-03-30 | 1993-08-17 | Hewlett-Packard Company | On-line acoustic densitometry tool for use with an ultrasonic imaging system |
DE4220633C1 (en) | 1992-06-24 | 1994-02-03 | Wolf Gmbh Richard | Device for supplying light to endoscopes |
US5733721A (en) | 1992-11-20 | 1998-03-31 | The Board Of Regents Of The University Of Oklahoma | Cell analysis method using quantitative fluorescence image analysis |
US5514127A (en) | 1993-02-18 | 1996-05-07 | Central Research Laboratories Limited | Apparatus for irradiating an area with a controllable pattern of light |
US5437274A (en) | 1993-02-25 | 1995-08-01 | Gholam A. Peyman | Method of visualizing submicron-size vesicles and particles in blood circulation |
JP3228627B2 (en) | 1993-03-19 | 2001-11-12 | オリンパス光学工業株式会社 | Endoscope image processing device |
US5431161A (en) | 1993-04-15 | 1995-07-11 | Adac Laboratories | Method and apparatus for information acquistion, processing, and display within a medical camera system |
US5421339A (en) | 1993-05-12 | 1995-06-06 | Board Of Regents, The University Of Texas System | Diagnosis of dysplasia using laser induced fluoroescence |
WO1996009792A1 (en) | 1993-05-17 | 1996-04-04 | The Johns Hopkins University | Improved visualization of choroidal blood flow and aberrant vascular structures in the eye |
US5394199A (en) | 1993-05-17 | 1995-02-28 | The Johns Hopkins University | Methods and apparatus for improved visualization of choroidal blood flow and aberrant vascular structures in the eye using fluorescent dye angiography |
US5424841A (en) | 1993-05-28 | 1995-06-13 | Molecular Dynamics | Apparatus for measuring spatial distribution of fluorescence on a substrate |
US5673701A (en) | 1994-10-07 | 1997-10-07 | Non Invasive Technology, Inc. | Optical techniques for examination of biological tissue |
DK75593D0 (en) | 1993-06-25 | 1993-06-25 | Novo Nordisk As | |
US5365057A (en) | 1993-07-02 | 1994-11-15 | Litton Systems, Inc. | Light-weight night vision device |
US5371355A (en) | 1993-07-30 | 1994-12-06 | Litton Systems, Inc. | Night vision device with separable modular image intensifier assembly |
JP3224640B2 (en) | 1993-07-30 | 2001-11-05 | 三菱重工業株式会社 | Apparatus and method for measuring concentration by LIF |
JPH0765154A (en) | 1993-08-31 | 1995-03-10 | Toshiba Corp | Device and method for quantitatively analyzing blood vessel image |
JPH0779955A (en) | 1993-09-14 | 1995-03-28 | Toshiba Corp | Radiographic apparatus |
JPH07155290A (en) | 1993-12-03 | 1995-06-20 | Olympus Optical Co Ltd | Endoscope apparatus |
JPH07155291A (en) | 1993-12-03 | 1995-06-20 | Olympus Optical Co Ltd | Fluorescence observation apparatus |
JP3487933B2 (en) | 1993-12-03 | 2004-01-19 | オリンパス株式会社 | Fluorescence observation device |
JP3283128B2 (en) | 1993-12-03 | 2002-05-20 | オリンパス光学工業株式会社 | Fluorescence observation endoscope device |
JPH07222712A (en) | 1994-02-10 | 1995-08-22 | Olympus Optical Co Ltd | Fluorescent endoscope system |
JP3194660B2 (en) | 1993-12-03 | 2001-07-30 | オリンパス光学工業株式会社 | Fluorescence observation device |
JP3285265B2 (en) | 1993-12-03 | 2002-05-27 | オリンパス光学工業株式会社 | Fluorescence observation device |
US5453448A (en) | 1993-12-09 | 1995-09-26 | Pdt Cardiovascular, Inc. | In vivo method for estimating the lipid contant of an atheromatous lesion |
JP3275159B2 (en) | 1993-12-17 | 2002-04-15 | 日本光電工業株式会社 | Circulating blood volume measurement device |
US5656498A (en) | 1994-02-22 | 1997-08-12 | Nippon Telegraph And Telephone Corporation | Freeze-dried blood cells, stem cells and platelets, and manufacturing method for the same |
US5707986A (en) | 1994-03-14 | 1998-01-13 | Miller; Joan W. | Angiographic method using green porphyrins in primate eyes |
JPH07250804A (en) | 1994-03-15 | 1995-10-03 | Olympus Optical Co Ltd | Fluorescence observer |
JPH07250812A (en) | 1994-03-15 | 1995-10-03 | Olympus Optical Co Ltd | Fluorescence diagnosing apparatus |
US5491343A (en) | 1994-03-25 | 1996-02-13 | Brooker; Gary | High-speed multiple wavelength illumination source, apparatus containing the same, and applications thereof to methods of irradiating luminescent samples and of quantitative luminescence ratio microscopy |
US5590660A (en) | 1994-03-28 | 1997-01-07 | Xillix Technologies Corp. | Apparatus and method for imaging diseased tissue using integrated autofluorescence |
AU2432795A (en) | 1994-05-03 | 1995-11-29 | Molecular Biosystems, Inc. | Composition for ultrasonically quantitating myocardial perfusion |
JP3641495B2 (en) | 1994-07-19 | 2005-04-20 | 株式会社日立メディコ | Medical diagnostic imaging equipment |
CA2141181A1 (en) | 1994-09-21 | 1996-03-22 | Kimberly-Clark Worldwide, Inc. | Wet-resilient webs |
EP0801534B1 (en) | 1994-09-26 | 2003-12-10 | The Johns Hopkins University | Improved visualization of choroidal blood flow and aberrant vascular structures in the eye |
US5627907A (en) | 1994-12-01 | 1997-05-06 | University Of Pittsburgh | Computerized detection of masses and microcalcifications in digital mammograms |
US5935942A (en) | 1994-12-14 | 1999-08-10 | Zeimer; Ran | Selective and non-invasive visualization or treatment of vasculature |
US5951980A (en) | 1995-01-06 | 1999-09-14 | Leuven Research & Development Vzw | Identification, production and use of new staphylokinase derivatives with reduced immunogenicity |
GB9502065D0 (en) | 1995-02-02 | 1995-03-22 | Nycomed Imaging As | Contrast media |
JPH08224208A (en) | 1995-02-22 | 1996-09-03 | Olympus Optical Co Ltd | Fluorescence observing endoscope device |
JPH08224240A (en) | 1995-02-22 | 1996-09-03 | Olympus Optical Co Ltd | Fluorescent diagnosing device |
JP3560671B2 (en) | 1995-02-23 | 2004-09-02 | オリンパス株式会社 | Fluorescence observation device |
JP3411737B2 (en) | 1995-03-03 | 2003-06-03 | ペンタックス株式会社 | Biological fluorescence diagnostic equipment |
US7236815B2 (en) | 1995-03-14 | 2007-06-26 | The Board Of Regents Of The University Of Texas System | Method for probabilistically classifying tissue in vitro and in vivo using fluorescence spectroscopy |
US5576013A (en) | 1995-03-21 | 1996-11-19 | Eastern Virginia Medical School | Treating vascular and neoplastic tissues |
CA2215978A1 (en) | 1995-04-04 | 1996-10-10 | Wound Healing Of Oklahoma | Cancer treatment by photodynamic therapy, in combination with an immunoadjuvant |
US5689241A (en) | 1995-04-24 | 1997-11-18 | Clarke, Sr.; James Russell | Sleep detection and driver alert apparatus |
US5743266A (en) | 1995-04-25 | 1998-04-28 | Molecular Biosystems, Inc. | Method for processing real-time contrast enhanced ultrasonic images |
US5623930A (en) | 1995-05-02 | 1997-04-29 | Acuson Corporation | Ultrasound system for flow measurement |
US6032070A (en) | 1995-06-07 | 2000-02-29 | University Of Arkansas | Method and apparatus for detecting electro-magnetic reflection from biological tissue |
JP3819032B2 (en) | 1995-08-24 | 2006-09-06 | ザ・テキサス・エイ・アンド・エム・ユニバーシティ・システム | Imaging and spectroscopic analysis based on fluorescence lifetime in tissues and other random media |
US5836311A (en) | 1995-09-20 | 1998-11-17 | Medtronic, Inc. | Method and apparatus for temporarily immobilizing a local area of tissue |
US5647368A (en) | 1996-02-28 | 1997-07-15 | Xillix Technologies Corp. | Imaging system for detecting diseased tissue using native fluorsecence in the gastrointestinal and respiratory tract |
US5756541A (en) | 1996-03-11 | 1998-05-26 | Qlt Phototherapeutics Inc | Vision through photodynamic therapy of the eye |
DE19613342A1 (en) | 1996-04-03 | 1997-10-09 | Philips Patentverwaltung | Automatic image evaluation process |
US5766127A (en) | 1996-04-15 | 1998-06-16 | Ohmeda Inc. | Method and apparatus for improved photoplethysmographic perfusion-index monitoring |
JPH09305845A (en) | 1996-05-13 | 1997-11-28 | Shibaura Eng Works Co Ltd | Hot vending machine |
US5662644A (en) | 1996-05-14 | 1997-09-02 | Mdlt, Inc. | Dermatological laser apparatus and method |
US5785965A (en) | 1996-05-15 | 1998-07-28 | The Board Of Trustees Of The Leland Stanford Junior Univ. | VEGF gene transfer into endothelial cells for vascular prosthesis |
JP3896176B2 (en) | 1996-05-21 | 2007-03-22 | 浜松ホトニクス株式会社 | Near-infrared fluorescent tracer and fluorescent imaging method |
GB9610700D0 (en) | 1996-05-22 | 1996-07-31 | Moor Instr Ltd | Apparatus for imaging microvascular blood flow |
JPH09308609A (en) | 1996-05-24 | 1997-12-02 | Canon Inc | Ophthalmologic image processor |
DE19635038A1 (en) | 1996-08-29 | 1998-03-12 | Pulsion Verwaltungs Gmbh & Co | Method for the non-invasive determination of cerebral blood flow by means of near infrared spectroscopy |
US5851181A (en) | 1996-08-30 | 1998-12-22 | Esc Medical Systems Ltd. | Apparatus for simultaneously viewing and spectrally analyzing a portion of skin |
JP2793989B2 (en) | 1996-09-30 | 1998-09-03 | オリンパス光学工業株式会社 | Rotating filter of light source device for endoscope |
JP3177635B2 (en) | 1996-09-30 | 2001-06-18 | 株式会社応用光電研究室 | Frequency standard and selection standard frequency generation method |
US6013265A (en) | 1996-10-22 | 2000-01-11 | University Of Maryland, Baltimore | Vaccine composition for herpes simplex virus and methods of using |
US6293911B1 (en) | 1996-11-20 | 2001-09-25 | Olympus Optical Co., Ltd. | Fluorescent endoscope system enabling simultaneous normal light observation and fluorescence observation in infrared spectrum |
JP3713347B2 (en) | 1996-11-25 | 2005-11-09 | オリンパス株式会社 | Fluorescence endoscope device |
JP3962122B2 (en) | 1996-11-20 | 2007-08-22 | オリンパス株式会社 | Endoscope device |
DE19648935B4 (en) | 1996-11-26 | 2008-05-15 | IMEDOS Intelligente Optische Systeme der Medizin- und Messtechnik GmbH | Device and method for the examination of vessels |
US6086539A (en) | 1996-12-04 | 2000-07-11 | Acuson Corporation | Methods and apparatus for ultrasound image quantification |
CA2192036A1 (en) | 1996-12-04 | 1998-06-04 | Harvey Lui | Fluorescence scope system for dermatologic diagnosis |
US6200310B1 (en) | 1997-01-08 | 2001-03-13 | Biosense, Inc. | Monitoring of myocardial revascularization |
JP3771985B2 (en) | 1997-01-20 | 2006-05-10 | オリンパス株式会社 | Fluorescence observation endoscope device |
JPH10210367A (en) | 1997-01-20 | 1998-08-07 | Olympus Optical Co Ltd | Electronic image-pickup device |
US5965356A (en) | 1997-01-31 | 1999-10-12 | University Of Maryland, Baltimore | Herpes simplex virus type specific seroassay |
US6122042A (en) | 1997-02-07 | 2000-09-19 | Wunderman; Irwin | Devices and methods for optically identifying characteristics of material objects |
US6466687B1 (en) | 1997-02-12 | 2002-10-15 | The University Of Iowa Research Foundation | Method and apparatus for analyzing CT images to determine the presence of pulmonary tissue pathology |
US6081612A (en) | 1997-02-28 | 2000-06-27 | Electro Optical Sciences Inc. | Systems and methods for the multispectral imaging and characterization of skin tissue |
US6008889A (en) | 1997-04-16 | 1999-12-28 | Zeng; Haishan | Spectrometer system for diagnosis of skin disease |
AU737530B2 (en) | 1997-04-17 | 2001-08-23 | Avimo Group Limited | Ocular microcirculation examination and treatment apparatus |
GB9710049D0 (en) | 1997-05-19 | 1997-07-09 | Nycomed Imaging As | Method |
US6280386B1 (en) | 1997-06-16 | 2001-08-28 | The Research Foundation Of The City University Of New York | Apparatus for enhancing the visibility of a luminous object inside tissue and methods for same |
AU7934498A (en) | 1997-06-27 | 1999-01-19 | Toa Medical Electronics Co., Ltd. | Living body inspecting apparatus and noninvasive blood analyzer using the same |
DE19747172C2 (en) | 1997-10-24 | 2000-04-13 | Pulsion Verwaltungs Gmbh & Co | Device for determining a pericardial effusion |
JP3370912B2 (en) | 1997-11-14 | 2003-01-27 | 松下電器産業株式会社 | Imaging device |
US6306642B1 (en) | 1997-11-24 | 2001-10-23 | Quidel Corporation | Enzyme substrate delivery and product registration in one step enzyme immunoassays |
JPH11155812A (en) | 1997-12-02 | 1999-06-15 | Olympus Optical Co Ltd | Fluorescent observation device |
US5919616A (en) | 1997-12-12 | 1999-07-06 | Aurx, Inc. | Serological assay for herpes |
JPH11183358A (en) | 1997-12-25 | 1999-07-09 | Kowa Co | Fluorescent grain image pickup container |
DE19800312A1 (en) | 1998-01-07 | 1999-07-08 | Wolf Gmbh Richard | Diagnostic device for imaging of fluorescent biological tissue areas |
US6054131A (en) | 1998-01-16 | 2000-04-25 | University Of Maryland Baltimore | Vaccine composition for herpes simplex virus and method of using |
US6113588A (en) | 1998-03-13 | 2000-09-05 | Corvascular, Inc. | Transillumination catheter and method |
AU756615B2 (en) | 1998-03-18 | 2003-01-16 | Medi-Physics, Inc. | MR methods for imaging pulmonary and cardiac vasculature and evaluating blood flow using dissolved polarized 129Xe |
US6462770B1 (en) | 1998-04-20 | 2002-10-08 | Xillix Technologies Corp. | Imaging system with automatic gain control for reflectance and fluorescence endoscopy |
US6399354B1 (en) | 1998-07-31 | 2002-06-04 | President And Fellows Of Harvard College | Replication-competent virus expressing a detectable fusion protein |
US6178340B1 (en) | 1998-08-24 | 2001-01-23 | Eduardo Svetliza | Three-dimensional infrared imager for subcutaneous puncture and study of vascular network |
CA2413033A1 (en) | 1998-09-18 | 2000-03-30 | Schering Aktiengesellschaft | Near infrared fluorescent contrast agent and fluorescence imaging |
US6162242A (en) | 1999-01-21 | 2000-12-19 | Peyman; Gholam A. | Selective photodynamic treatment |
AU3349200A (en) | 1999-01-26 | 2000-08-07 | Newton Laboratories, Inc. | Autofluorescence imaging system for endoscopy |
GB9903394D0 (en) | 1999-02-15 | 1999-04-07 | Avimo Group Limited | Treatment of neovascularization and other eye diseases |
US6167297A (en) | 1999-05-05 | 2000-12-26 | Benaron; David A. | Detecting, localizing, and targeting internal sites in vivo using optical contrast agents |
US6217848B1 (en) | 1999-05-20 | 2001-04-17 | Mallinckrodt Inc. | Cyanine and indocyanine dye bioconjugates for biomedical applications |
US6186628B1 (en) | 1999-05-23 | 2001-02-13 | Jozek F. Van de Velde | Scanning laser ophthalmoscope for selective therapeutic laser |
US6944493B2 (en) | 1999-09-10 | 2005-09-13 | Akora, Inc. | Indocyanine green (ICG) compositions and related methods of use |
WO2001017561A1 (en) | 1999-09-10 | 2001-03-15 | Akorn, Inc. | Fluorescent dye angiography and dye-enhanced photocoagulation |
US20050182434A1 (en) | 2000-08-11 | 2005-08-18 | National Research Council Of Canada | Method and apparatus for performing intra-operative angiography |
EP1852063B1 (en) | 1999-09-24 | 2011-04-20 | National Research Council Of Canada | Apparatus for performing intra-operative angiography |
US7581191B2 (en) | 1999-11-15 | 2009-08-25 | Xenogen Corporation | Graphical user interface for 3-D in-vivo imaging |
JP2001147387A (en) | 1999-11-22 | 2001-05-29 | Asahi Optical Co Ltd | Scanning optical device |
AU1547101A (en) | 1999-11-26 | 2001-06-04 | Applied Spectral Imaging Ltd. | System and method for functional brain mapping and an oxygen saturation difference map algorithm for effecting same |
US6443976B1 (en) | 1999-11-30 | 2002-09-03 | Akorn, Inc. | Methods for treating conditions and illnesses associated with abnormal vasculature |
AT409451B (en) | 1999-12-14 | 2002-08-26 | Hoffmann La Roche | DEVICE FOR DETERMINING THE LOCAL DISTRIBUTION OF A MEASURED VALUE |
US6319273B1 (en) | 1999-12-16 | 2001-11-20 | Light Sciences Corporation | Illuminating device for treating eye disease |
US6603552B1 (en) | 1999-12-22 | 2003-08-05 | Xillix Technologies Corp. | Portable system for detecting skin abnormalities based on characteristic autofluorescence |
JP2001198079A (en) | 2000-01-19 | 2001-07-24 | Fuji Photo Film Co Ltd | Fluorescent diagnostic device |
US6447443B1 (en) | 2001-01-13 | 2002-09-10 | Medtronic, Inc. | Method for organ positioning and stabilization |
CA2401270A1 (en) | 2000-03-10 | 2001-09-20 | Jeff W. Lichtman | Method for labeling individual cells |
GB0010123D0 (en) | 2000-04-27 | 2000-06-14 | Univ Nottingham | Planar light sheet anemometers |
US6889075B2 (en) | 2000-05-03 | 2005-05-03 | Rocky Mountain Biosystems, Inc. | Optical imaging of subsurface anatomical structures and biomolecules |
DE10028233A1 (en) | 2000-06-07 | 2002-01-24 | Cobra Electronic Gmbh | Colour camera has slide with infrared or optical filters provides day and night modes |
CA2418179A1 (en) | 2000-07-26 | 2002-01-31 | University Of Maryland, Baltimore | The protein kinase domain of the large subunit of herpes simplex type 2 ribonucleotide reductase (icp10pk) has anti-apoptopic activity |
US6669926B1 (en) | 2000-10-16 | 2003-12-30 | Mallinckrodt, Inc. | Hydrophilic light absorbing indole compounds for determination of physiological function in critically ill patients |
US6869437B1 (en) | 2000-11-13 | 2005-03-22 | Cardica, Inc. | Method and system for performing closed-chest bypass |
DE10059070C1 (en) | 2000-11-28 | 2002-02-14 | Pulsion Medical Sys Ag | Device for determining tissue perfusion has source and expansion optics arranged in safety housing so only expanded beam of intensity within safety limits for persons near device emanates |
DE60236068D1 (en) | 2001-01-31 | 2010-06-02 | Mayo Foundation | PROOF OF HERPEX SIMPLEX VIRUS |
US20020181752A1 (en) | 2001-03-14 | 2002-12-05 | Warren Wallo | Method for measuring changes in portions of a human body |
AU2002305148A1 (en) | 2001-04-05 | 2002-10-21 | Johns Hopkins University | Imaging systems for in vivo protocols |
US6757554B2 (en) | 2001-05-22 | 2004-06-29 | Alfred E. Mann Institute For Biomedical Engineering At The University Of Southern California | Measurement of cardiac output and blood volume by non-invasive detection of indicator dilution |
EP1406081A4 (en) | 2001-07-03 | 2011-10-05 | Hitachi Ltd | Biological sample optical measuring method and biological sample optical measuring apparatus |
WO2003006658A1 (en) | 2001-07-13 | 2003-01-23 | The General Hospital Corporation | Mutant herpes simplex virus that expresses yeast cytosine deaminase |
US6544183B2 (en) | 2001-08-02 | 2003-04-08 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Method for imaging skin surface intercellular and intracellular structure using a compound to enhance contrast |
DE10143995A1 (en) | 2001-09-07 | 2003-04-03 | Pulsion Medical Sys Ag | System and computer program for determining a patient's circulatory parameters |
US7113817B1 (en) | 2001-10-04 | 2006-09-26 | Wintec, Llc | Optical imaging of blood circulation velocities |
US6936043B2 (en) | 2001-11-13 | 2005-08-30 | Minu, Llc | Method to treat age-related macular degeneration |
US6942655B2 (en) | 2001-11-13 | 2005-09-13 | Minu, Llc | Method to treat age-related macular degeneration |
JP3753650B2 (en) | 2001-11-14 | 2006-03-08 | 株式会社島津製作所 | Blood flow measuring device |
EP1332718A1 (en) | 2002-02-01 | 2003-08-06 | Stichting Voor De Technische Wetenschappen | Laser doppler perfusion imaging using a CMOS image sensor |
WO2003068959A1 (en) | 2002-02-14 | 2003-08-21 | Takeda Chemical Industries, Ltd. | Novel screening method |
US7404640B2 (en) | 2002-06-14 | 2008-07-29 | Physical Sciences, Inc. | Monitoring blood flow in the retina using a line-scanning laser ophthalmoscope |
JP4515721B2 (en) | 2002-06-21 | 2010-08-04 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | Method, apparatus and software for analyzing perfusion images |
WO2004006963A1 (en) | 2002-07-12 | 2004-01-22 | Beth Israel Deaconess Medical Center | Conjugated infrared fluorescent substances for detection of cell death |
US7897336B2 (en) * | 2002-08-16 | 2011-03-01 | John Wayne Cancer Institute | Molecular lymphatic mapping of sentinel lymph nodes |
US20040077952A1 (en) | 2002-10-21 | 2004-04-22 | Rafter Patrick G. | System and method for improved diagnostic image displays |
JP2006519032A (en) | 2002-12-02 | 2006-08-24 | エダ リサーチ アンド ディベロップメント カンパニー リミティド | Characterization of arteriosclerosis by optical imaging |
DE10257743B4 (en) | 2002-12-10 | 2006-11-23 | Irmgard Zerrle | Device for determining perfusion in a tissue region and blood flow through individual blood vessels |
JP2004325200A (en) | 2003-04-24 | 2004-11-18 | Hitachi Ltd | In-tissue material concentration measuring apparatus |
WO2005002425A2 (en) | 2003-07-02 | 2005-01-13 | U.S. Government As Represented By The Secretary Of The Army | Wearable tissue viability diagnostic unit |
US20050019744A1 (en) | 2003-07-25 | 2005-01-27 | La Jolla Bioengineering Institute | Ultrasound-assisted ischemic reperfusion |
US20070105220A1 (en) | 2003-08-06 | 2007-05-10 | The Regents Of The University Of California | Erythrocytic cells and method for loading solutes |
WO2005036143A1 (en) | 2003-10-10 | 2005-04-21 | Hamamatsu Photonics K.K. | Method and system for determining concentration of fluorescent pigment |
US7512436B2 (en) | 2004-02-12 | 2009-03-31 | The Regents Of The University Of Michigan | Method of evaluating metabolism of the eye |
WO2006014334A2 (en) | 2004-07-06 | 2006-02-09 | Advanced Biophotonics, Inc. | Systems and methods for localizing vascular architecture, and evaluation and monitoring of functional behavior of same |
US7899271B1 (en) | 2004-09-15 | 2011-03-01 | Raytheon Company | System and method of moving target based calibration of non-uniformity compensation for optical imagers |
US7477931B2 (en) | 2004-12-06 | 2009-01-13 | Cambridge Research & Instruments, Inc. | Systems and methods for in-vivo and optical imaging and measurement |
JP4937991B2 (en) | 2004-12-08 | 2012-05-23 | オリンパス株式会社 | Fluorescence endoscope apparatus and imaging unit used therefor |
JP5028008B2 (en) | 2004-12-08 | 2012-09-19 | オリンパス株式会社 | Fluorescence endoscope device |
WO2006069379A2 (en) | 2004-12-22 | 2006-06-29 | Bio-Tree Systems, Inc. | Medical imaging methods and apparatus for diagnosis and monitoring of diseases and uses therefor |
US7729750B2 (en) | 2005-01-20 | 2010-06-01 | The Regents Of The University Of California | Method and apparatus for high resolution spatially modulated fluorescence imaging and tomography |
FR2882147B1 (en) | 2005-02-14 | 2007-10-05 | Commissariat Energie Atomique | FLUORESCENCE IMAGING DEVICE BY TWO WAVE LENGTH REFLECTION |
EP1898792B1 (en) | 2005-04-14 | 2010-08-11 | Bracco Suisse SA | Perfusion assessment based on animated perfusion imaging |
WO2006111909A1 (en) | 2005-04-20 | 2006-10-26 | Cvl Cosmetics S.A. | Instrument and method for high-speed perfusion imaging |
US20130296715A1 (en) | 2005-04-20 | 2013-11-07 | Ecole Polytechnique Federale De Lausanne (Epfl) | Instrument and method for high-speed perfusion imaging |
WO2006116634A2 (en) | 2005-04-26 | 2006-11-02 | Novadaq Technologies, Inc. | Method and apparatus for vasculature visualization with applications in neurosurgery and neurology |
US20060239921A1 (en) | 2005-04-26 | 2006-10-26 | Novadaq Technologies Inc. | Real time vascular imaging during solid organ transplant |
US7918559B2 (en) | 2005-04-29 | 2011-04-05 | Novadaq Technologies Inc. | Choroid and retinal imaging and treatment system |
RU2288633C1 (en) | 2005-04-29 | 2006-12-10 | ГОУ ВПО "Красноярская государственная медицинская академия Федерального агентства по здравоохранению и социальному развитию" | Method for detecting the borders of resection in case of close trauma of pancreas along with the rupture of the main pancreatic duct |
US8460191B2 (en) | 2005-05-20 | 2013-06-11 | Hitachi Medical Corporation | Ultrasonic medical diagnostic device for imaging changes with time |
US7400755B2 (en) | 2005-06-02 | 2008-07-15 | Accuray Incorporated | Inverse planning using optimization constraints derived from image intensity |
JP2007021006A (en) | 2005-07-20 | 2007-02-01 | Hitachi Medical Corp | X-ray ct apparatus |
CA2618443A1 (en) | 2005-08-10 | 2007-02-15 | Novadaq Technologies, Inc. | Intra-operative head & neck nerve mapping |
US20070122344A1 (en) | 2005-09-02 | 2007-05-31 | University Of Rochester Medical Center Office Of Technology Transfer | Intraoperative determination of nerve location |
DE102005044531A1 (en) | 2005-09-16 | 2007-03-22 | Myrenne Gmbh | Indicator`s e.g. indocyanin green, perfusion distribution determining method, involves measuring intensity of light radiation or field by measuring device directed on tissue, and determining gradient of intensity as measure of perfusion |
US8340744B2 (en) | 2005-12-15 | 2012-12-25 | Koninklijke Philips Electronics N.V. | System, apparatus, and method for reproducible and comparable flow acquisitions |
US20070254276A1 (en) | 2006-04-26 | 2007-11-01 | Seng Enterprises Ltd. | Method and system for measuring membrane potential based on fluorescence polarization |
DE102006025423A1 (en) | 2006-05-31 | 2007-12-06 | Siemens Ag | X-ray arrangement operating method, involves storing projection images that correspond with energy spectra, which are different from one another, where one spectra lies above and below energy barrier that amounts to specific volts |
US9220411B2 (en) | 2006-06-01 | 2015-12-29 | The General Hospital Corporation | In-vivo optical imaging method including analysis of dynamic images |
US20080025918A1 (en) | 2006-07-03 | 2008-01-31 | Beth Israel Deaconess Medical Center, Inc. | Invisible light fluorescent platelets for intraoperative detection of vascular thrombosis |
WO2008076467A2 (en) | 2006-07-03 | 2008-06-26 | Beth Israel Deaconess Medical Center, Inc. | Intraoperative imaging methods |
US7450243B2 (en) | 2006-07-10 | 2008-11-11 | The Board Of Trustees Of The University Of Illinois | Volumetric endoscopic coherence microscopy using a coherent fiber bundle |
US9089601B2 (en) * | 2006-07-10 | 2015-07-28 | University Of Rochester | Pre- and intra-operative imaging of bladder cancer |
US8078265B2 (en) | 2006-07-11 | 2011-12-13 | The General Hospital Corporation | Systems and methods for generating fluorescent light images |
US8725225B2 (en) * | 2006-08-10 | 2014-05-13 | University Of Rochester | Intraoperative imaging of renal cortical tumors and cysts |
US20080161744A1 (en) | 2006-09-07 | 2008-07-03 | University Of Rochester Medical Center | Pre-And Intra-Operative Localization of Penile Sentinel Nodes |
US20080081990A1 (en) | 2006-09-28 | 2008-04-03 | The Research Foundation Of State University Of New York | Apparatus, system, kit and method for heart mapping |
US11540720B2 (en) | 2006-10-06 | 2023-01-03 | Stryker European Operations Limited | Methods, software and systems for imaging |
KR100867977B1 (en) | 2006-10-11 | 2008-11-10 | 한국과학기술원 | Machine to analyze tissue perfusion using concentration of indocyanine green in blood and a method for analysing tissue perfusion using the same |
US8498695B2 (en) | 2006-12-22 | 2013-07-30 | Novadaq Technologies Inc. | Imaging system with a single color image sensor for simultaneous fluorescence and color video endoscopy |
JP4954699B2 (en) | 2006-12-28 | 2012-06-20 | オリンパス株式会社 | Fluorescence endoscope system |
EP2096429A4 (en) | 2007-01-16 | 2009-12-16 | Olympus Corp | Fluorescent signal analyzing apparatus and fluorescent signal analyzing method |
KR100818669B1 (en) | 2007-03-09 | 2008-04-02 | 한국과학기술원 | Apparatus for measuring the perfusion rate of legs |
DE102007014133B4 (en) | 2007-03-23 | 2015-10-29 | Siemens Aktiengesellschaft | A method of visualizing a sequence of tomographic volume data sets of medical imaging |
EP2129283A1 (en) | 2007-03-23 | 2009-12-09 | Enverdis GmbH | Method for determining microvascular lesions |
DE102007063626A1 (en) | 2007-04-19 | 2009-09-10 | Carl Zeiss Surgical Gmbh | Method and apparatus for displaying a field of a brain of a patient and navigation system for brain operations |
CN101784227B (en) | 2007-07-06 | 2013-12-04 | 工业研究有限公司 | Laser speckle imaging systems and methods |
US8073224B2 (en) | 2007-07-09 | 2011-12-06 | Siemens Aktiengesellschaft | System and method for two-dimensional visualization of temporal phenomena and three dimensional vessel reconstruction |
DE102007048362B9 (en) | 2007-10-09 | 2017-08-17 | Carl Zeiss Meditec Ag | System and method for examining an object |
AU2009204461A1 (en) | 2008-01-10 | 2009-07-16 | Pacific Biosciences Of California, Inc. | Methods and systems for analysis of fluorescent reactions with modulated excitation |
US8406860B2 (en) | 2008-01-25 | 2013-03-26 | Novadaq Technologies Inc. | Method for evaluating blush in myocardial tissue |
JP5476317B2 (en) | 2008-01-25 | 2014-04-23 | ノバダック テクノロジーズ インコーポレイテッド | Method and system for assessing brush in myocardial tissue |
US20140316262A1 (en) | 2008-02-26 | 2014-10-23 | Novadaq Technologies Inc. | Preoperative identification of perforator vessels in flaps to be used in reconstructive surgery |
JP5231625B2 (en) | 2008-03-18 | 2013-07-10 | ノヴァダク テクノロジーズ インコーポレイテッド | Imaging system for acquiring NIR and full color images and method of operation thereof |
JP5074256B2 (en) | 2008-03-24 | 2012-11-14 | オリンパス株式会社 | Fluorescence observation equipment |
EP2268201B1 (en) | 2008-04-14 | 2017-05-17 | Novadaq Technologies Inc. | Evaluation of perfusion of perforator vessels |
US10219742B2 (en) | 2008-04-14 | 2019-03-05 | Novadaq Technologies ULC | Locating and analyzing perforator flaps for plastic and reconstructive surgery |
ES2671710T3 (en) | 2008-05-02 | 2018-06-08 | Novadaq Technologies ULC | Methods for the production and use of erythrocytes loaded with substances for the observation and treatment of microvascular hemodynamics |
MX2010012035A (en) | 2008-05-14 | 2011-02-23 | Novadaq Technologies Inc | Imaging methods and compositions comprising fluorescent dyes associated with viral components for nerve imaging. |
US8150127B2 (en) | 2008-05-28 | 2012-04-03 | Siemens Medical Solutions Usa, Inc. | Method for automatically synchronizing the review of two DSA scenes |
JP5389382B2 (en) | 2008-06-09 | 2014-01-15 | オリンパス株式会社 | Fluorescence endoscope device |
DE102008040804B4 (en) | 2008-07-28 | 2021-07-29 | Carl Zeiss Meditec Ag | Method, surgical microscope and analysis system for the quantitative representation of blood flow |
US8144958B2 (en) | 2008-09-11 | 2012-03-27 | Carl Zeiss Meditec Ag | Medical systems and methods |
US10492671B2 (en) | 2009-05-08 | 2019-12-03 | Novadaq Technologies ULC | Near infra red fluorescence imaging for visualization of blood vessels during endoscopic harvest |
US20110071403A1 (en) | 2009-09-21 | 2011-03-24 | Board Of Regents Of The University Of Texas System | Functional near-infrared fluorescence lymphatic mapping for diagnosing, accessing, monitoring and directing therapy of lymphatic disorders |
US9091903B2 (en) | 2010-07-29 | 2015-07-28 | Logitech Europe S.A. | Optimized movable IR filter in cameras |
WO2012029269A1 (en) | 2010-09-02 | 2012-03-08 | 国立大学法人東北大学 | Method for determining cancer onset or cancer onset risk |
JP5682976B2 (en) | 2010-09-17 | 2015-03-11 | 国立大学法人東北大学 | Method for determining the effectiveness of pharmaceuticals containing antibodies as components |
JP5371946B2 (en) | 2010-12-24 | 2013-12-18 | 富士フイルム株式会社 | Endoscopic diagnosis device |
US9226673B2 (en) | 2011-01-10 | 2016-01-05 | East Carolina University | Methods, systems and computer program products for non-invasive determination of blood flow distribution using speckle imaging techniques and hemodynamic modeling |
EP2663222B1 (en) | 2011-01-10 | 2021-10-27 | East Carolina University | Methods and systems for non-invasive determination of blood flow distribution using speckle imaging techniques and hemodynamic modeling |
US9179843B2 (en) | 2011-04-21 | 2015-11-10 | Hassan Ghaderi MOGHADDAM | Method and system for optically evaluating proximity to the inferior alveolar nerve in situ |
JP5991975B2 (en) | 2011-06-29 | 2016-09-14 | 京都府公立大学法人 | Tumor site identification device and identification method |
CA2914778A1 (en) | 2012-06-21 | 2013-12-27 | Novadaq Technologies Inc. | Quantification and analysis of angiography and perfusion |
US9575304B2 (en) | 2012-06-25 | 2017-02-21 | Huron Technologies International Inc. | Pathology slide scanners for fluorescence and brightfield imaging and method of operation |
US9449377B2 (en) | 2012-10-09 | 2016-09-20 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Imaging methods and computer-readable media |
JP6198426B2 (en) | 2013-03-29 | 2017-09-20 | 浜松ホトニクス株式会社 | Fluorescence observation apparatus and fluorescence observation method |
WO2015001427A2 (en) | 2013-06-14 | 2015-01-08 | Novadaq Technologies Inc. | Quantification of absolute blood flow in tissue using fluorescence mediated photoplethysmography |
US9779500B2 (en) | 2013-07-03 | 2017-10-03 | Konica Minolta, Inc. | Image processing device, pathological diagnosis support system, image processing program, and pathological diagnosis support method |
WO2015186397A1 (en) | 2014-06-05 | 2015-12-10 | オリンパスメディカルシステムズ株式会社 | Processing device, endoscope system, endoscope device, image processing method, and image processing program |
AU2015327665B2 (en) | 2014-09-29 | 2018-09-27 | Stryker European Operations Limited | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
KR101955134B1 (en) | 2014-10-09 | 2019-03-06 | 노바다크 테크놀러지즈 유엘씨 | Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography |
JP6931705B2 (en) | 2017-02-10 | 2021-09-08 | ノバダック テクノロジーズ ユーエルシー | Open Field Handheld Fluorescence Imaging Systems and Methods |
-
2007
- 2007-09-06 US US11/851,312 patent/US20080161744A1/en not_active Abandoned
- 2007-09-07 WO PCT/US2007/077892 patent/WO2008031038A2/en active Application Filing
-
2017
- 2017-05-31 US US15/610,102 patent/US10434190B2/en active Active
Patent Citations (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5438989A (en) * | 1990-08-10 | 1995-08-08 | Hochman; Darryl | Solid tumor, cortical function, and nerve tissue imaging methods and device |
US5465718A (en) * | 1990-08-10 | 1995-11-14 | Hochman; Daryl | Solid tumor, cortical function, and nerve tissue imaging methods and device |
US6671540B1 (en) * | 1990-08-10 | 2003-12-30 | Daryl W. Hochman | Methods and systems for detecting abnormal tissue using spectroscopic techniques |
US5699798A (en) * | 1990-08-10 | 1997-12-23 | University Of Washington | Method for optically imaging solid tumor tissue |
US6196226B1 (en) * | 1990-08-10 | 2001-03-06 | University Of Washington | Methods and apparatus for optically imaging neuronal tissue and activity |
US6233480B1 (en) * | 1990-08-10 | 2001-05-15 | University Of Washington | Methods and apparatus for optically imaging neuronal tissue and activity |
US6241672B1 (en) * | 1990-08-10 | 2001-06-05 | University Of Washington | Method and apparatus for optically imaging solid tumor tissue |
US5149671A (en) * | 1990-12-03 | 1992-09-22 | Grumman Aerospace Corporation | Method for forming multilayer indium bump contact |
US6485413B1 (en) * | 1991-04-29 | 2002-11-26 | The General Hospital Corporation | Methods and apparatus for forward-directed optical scanning instruments |
US20020146369A1 (en) * | 1992-05-06 | 2002-10-10 | Immunomedics, Inc. | Intraoperative, intravascular and endoscopic tumor and lesion detection, biopsy and therapy |
US5279298A (en) * | 1992-11-20 | 1994-01-18 | The Johns Hopkins University | Method and apparatus to identify and treat neovascular membranes in the eye |
US5496369A (en) * | 1994-02-09 | 1996-03-05 | University Of Iowa Research Foundation | Human cerebral cortex neural prosthetic |
US5519534A (en) * | 1994-05-25 | 1996-05-21 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Irradiance attachment for an optical fiber to provide a uniform level of illumination across a plane |
US6335429B1 (en) * | 1997-10-10 | 2002-01-01 | Cytovia, Inc. | Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof |
US20050197583A1 (en) * | 1998-02-11 | 2005-09-08 | Britton Chance | Detection, imaging and characterization of breast tumors |
US6331703B1 (en) * | 1999-03-12 | 2001-12-18 | Ethicon Endo-Surgery, Inc. | Guidance method for radiation detection |
US20030236458A1 (en) * | 1999-08-03 | 2003-12-25 | Biophysica Llc | Spectroscopic systems and methods for detecting tissue properties |
US6351663B1 (en) * | 1999-09-10 | 2002-02-26 | Akorn, Inc. | Methods for diagnosing and treating conditions associated with abnormal vasculature using fluorescent dye angiography and dye-enhanced photocoagulation |
US6915154B1 (en) * | 1999-09-24 | 2005-07-05 | National Research Council Of Canada | Method and apparatus for performing intra-operative angiography |
US20050107380A1 (en) * | 2000-01-18 | 2005-05-19 | Nimmo Alan J. | Brain, spinal and nerve injury treatment |
US6804549B2 (en) * | 2000-04-25 | 2004-10-12 | Fuji Photo Film Co., Ltd. | Sentinel lymph node detection method and system therefor |
US6821946B2 (en) * | 2000-05-10 | 2004-11-23 | University College London | Repair of nerve damage |
US6853857B2 (en) * | 2001-05-01 | 2005-02-08 | Pulsion Medical Systems Ag | Method, device and computer program for determining the blood flow in a tissue or organ region |
US20040174495A1 (en) * | 2001-06-05 | 2004-09-09 | Adaptive Optics Associates, Inc. | Method of and system for examining the human eye with a wavefront sensor-based ophthalmic instrument |
US20030156252A1 (en) * | 2001-10-19 | 2003-08-21 | Morris Robert E. | Macula cover and method |
US20050069525A1 (en) * | 2001-11-16 | 2005-03-31 | Wiberg Mikael | Nerve repair unit and method of producing it |
US6899675B2 (en) * | 2002-01-15 | 2005-05-31 | Xillix Technologies Corp. | Fluorescence endoscopy video systems with no moving parts in the camera |
US20050182321A1 (en) * | 2002-03-12 | 2005-08-18 | Beth Israel Deaconess Medical Center | Medical imaging systems |
US20030187349A1 (en) * | 2002-03-29 | 2003-10-02 | Olympus Optical Co., Ltd. | Sentinel lymph node detecting method |
US20030232016A1 (en) * | 2002-04-17 | 2003-12-18 | Russell Heinrich | Nerve identification and sparing method |
US20040206364A1 (en) * | 2002-07-17 | 2004-10-21 | Robert Flower | Combined photocoagulation and photodynamic therapy |
US20040109231A1 (en) * | 2002-08-28 | 2004-06-10 | Carl-Zeiss-Stiftung Trading As Carl Zeiss | Microscopy system, microscopy method and a method of treating an aneurysm |
US20040171827A1 (en) * | 2002-10-25 | 2004-09-02 | Li-Cor, Inc. | Phthalocyanine dyes |
US20040156782A1 (en) * | 2003-02-12 | 2004-08-12 | Akorn, Inc. | Methods of using indocyanine green (ICG) dye |
US20070203413A1 (en) * | 2003-09-15 | 2007-08-30 | Beth Israel Deaconess Medical Center | Medical Imaging Systems |
US20060013768A1 (en) * | 2004-07-13 | 2006-01-19 | Woltering Eugene A | Injection of a radioactive dye for sentinel lymph node identification |
US7381400B2 (en) * | 2004-07-13 | 2008-06-03 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Injection of a radioactive dye for sentinel lymph node identification |
US20060108509A1 (en) * | 2004-09-09 | 2006-05-25 | Frangioni John V | Systems and methods for multi-modal imaging |
US20060241499A1 (en) * | 2005-02-24 | 2006-10-26 | Irion Klaus M | Multifunctional fluorescence diagnosis system |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8825140B2 (en) | 2001-05-17 | 2014-09-02 | Xenogen Corporation | Imaging system |
US10265419B2 (en) | 2005-09-02 | 2019-04-23 | Novadaq Technologies ULC | Intraoperative determination of nerve location |
US10434190B2 (en) | 2006-09-07 | 2019-10-08 | Novadaq Technologies ULC | Pre-and-intra-operative localization of penile sentinel nodes |
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US20140267603A1 (en) * | 2013-03-15 | 2014-09-18 | Intuitive Surgical Operations, Inc. | Depth based modification of captured images |
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US9816930B2 (en) | 2014-09-29 | 2017-11-14 | Novadaq Technologies Inc. | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
US10631746B2 (en) | 2014-10-09 | 2020-04-28 | Novadaq Technologies ULC | Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography |
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US11140305B2 (en) | 2017-02-10 | 2021-10-05 | Stryker European Operations Limited | Open-field handheld fluorescence imaging systems and methods |
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US20180104362A1 (en) | 2018-04-19 |
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WO2008031038A3 (en) | 2008-08-21 |
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