US20050287065A1 - Systems, methods and devices for in vivo monitoring of a localized response via a radiolabeled analyte in a subject - Google Patents

Systems, methods and devices for in vivo monitoring of a localized response via a radiolabeled analyte in a subject Download PDF

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US20050287065A1
US20050287065A1 US11208983 US20898305A US2005287065A1 US 20050287065 A1 US20050287065 A1 US 20050287065A1 US 11208983 US11208983 US 11208983 US 20898305 A US20898305 A US 20898305A US 2005287065 A1 US2005287065 A1 US 2005287065A1
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radiation
configured
labeled
glucose
vivo
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Steven Suddarth
Charles Scarantino
Robert Black
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VTQ IP HOLDING Corp
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Sicel Technologies Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/0491Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/02Devices for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03Computerised tomographs
    • A61B6/037Emission tomography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/48Diagnostic techniques
    • A61B6/486Diagnostic techniques involving generating temporal series of image data
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/50Clinical applications
    • A61B6/507Clinical applications involving determination of haemodynamic parameters, e.g. perfusion CT
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/0004Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/50Clinical applications
    • A61B6/508Clinical applications for non-human patients

Abstract

System for analyzing an in vivo response of a subject include a radiation detector for detecting radiation present in at least one localized solid tissue region of interest in a subject associated with internal activity of an administered quantity of an analyte comprising at least one of C-14 labeled glucose, a C-14 labeled constituent thereof, and a C-14 labeled glucose derivative, in the at least one solid tissue region of interest over a desired time interval of interest; and a reader in communication with the implantable detector for collecting radiation data from the detector associated with the detected radiation to determine at least one of the following; the in vivo dynamic, kinetic, and metabolic response of the subject.

Description

    RELATED APPLICATION
  • This application is a divisional of U.S. patent application Ser. No. 10/127,207 filed Apr. 22, 2002, which claims priority from U.S. Provisional Patent Application Ser. No. 60/285,923, filed Apr. 23, 2001, the contents of which are hereby incorporated by reference as if recited in full herein.
  • FIELD OF THE INVENTION
  • The present invention is related to systems and methods for monitoring radiation and/or metabolic activity in a subject.
  • BACKGROUND OF THE INVENTION
  • One of the major problems in the management of the cancer patient is the predictability or determination of therapy response prior to the initiation of treatment. This can be particularly important for the patient receiving chemotherapy. The conventional approaches in the determination of the treatment protocol (to establish a treatment agent or drug(s) regimen) to be used in the treatment of specific tumor type remains largely empirical. That is, the conventional therapeutic approach is to utilize what is considered to be the most effective treatment as determined by prospective randomized trials across a sampled population. This approach overlooks the fact that, as each patient is different, so is each patient's tumor and/or response to the treatment selected. The biological and physiological uniqueness of each patient is not considered nor is the potential for an individualized therapeutic approach. See generally Kastrissios et al., Screening for Sources of Interindividual Pharmacokinetic Variability in Anticancer Drug Therapy: Utility of Population Analysis, Cancer Investigation, 19(1), 57-64 (2001).
  • Both the need for and potential benefits of a predictive test for a patient's response to a particular treatment protocol, particularly for the cancer patient, have long been recognized. The benefits include (a) an increased chance for tumor response from initial effective therapy, (b) a reduction in the potential for development of resistant cells when less effective therapy is given (c) a decreased morbidity associated with non effective therapy, and (d) an improved probability of cure or positive outcome with the timely administration of effective therapy. It is generally accepted that the initial treatment approach is the most important to obtain the best tumor response. Second and third line therapies are typically less effective and primarily palliative. Therefore, the availability of a method to determine the most appropriate and effective drug (s) prior to the initiation of therapy may allow for a maximum response. That is, if, for a given tumor, several drugs have been shown to be effective in large clinical trials, the question as to which one (s) to use in a particular patient can be important. Since, as noted above, differences do exist between individual tumors of the same site, choosing the most effective therapeutic agents should increase the likelihood of a beneficial response and reduce the chance for the development of a resistant cell population. It may also reduce the possibility of utilizing a particular drug as a second or third line therapy, when its effectiveness may be reduced because of the development of drug resistant populations.
  • An important additional benefit to the patient may be a lower morbidity rate than that which is associated with a “try and see” approach (that is, to “try” a specific regimen and “see” how the patient responds). A knowledge of effective drugs may reduce the morbidity of therapy, since it will offer the patient an increased chance for response and/or reduce the need for second and third line therapies.
  • The early attempts to establish predictive tests were dependent on the availability of cell culture techniques and cell lines. The tests included evaluation of cell morphology, exclusion of vital dyes, and incorporation of radioactive precursor molecules after incubation of tumor cells with anticancer agents. The primary problem was a lack of predictive value in most correlative studies. See, e.g., Yarnell et al., Drug Assays on Organ Cultures of Biopsies from Human Tumours, Br Med J 1964; 2:490-491. More recently, the culture of human tumors was reported by Hamburger et al., in Primary Bioassay of Human Tumor Stem Cells, Science 1977;197:461-463. Since its introduction, the Human Tumor Clonogenic Assay (HTCA) has been investigated as a predictive assay for human tumors. Contrary to the previously identified assays, inhibition of cellular proliferation is directly used as the experimental endpoint. In addition, it defines results in terms of chemoresistance and chemosensitivity. The cumulative results of over 2300 correlations between the HTCA and clinical response was reported by Von Hoff et al. in 1990. See Von Hoff et al., Selection of Cancer Chemotherapy for a Patient by an In Vitro Assay Versus a Clinician, JNCI 1990;82:110-116. The results revealed a 69% probability for a patient to have at least a partial response if the tumor specimen is sensitive to the drug in vitro. However, if the tumor is resistant in vitro, there appears to be a 91% chance for clinical resistance. The major technical problems with most clonogenic assays include the lack of growth in 40 to 60% of all specimens and a relatively long incubation time (generally on the order of at least 14 days) before results are available. In addition, there is insufficient data available on the effect of assay-guided chemotherapy on patient survival, and most clinically observed responses are partial responses.
  • More recently, a commercially available assay has alleged a 99% accuracy in prediction of clinical failure. The success of the assay purportedly results from extended exposure of the patient tumor cells to levels of chemotherapy agents, which approximate the peak plasma levels attained after conventional IV administration. If a patient's cells proliferate after extended exposure to peak plasma levels of chemotherapy agents, then it can be accurately predicted that these cells will also demonstrate resistance to normal exposures in vivo. However, the reported accuracy to predict chemo-sensitivity is only about 60-70%. Moreover, the assay method is not able to address tumor response over time or in real time. The sample represents the biology of only one point in time of the treatment history of each tumor; it does not consider conditions that effect drug delivery to the tumor, including poorly perfused tumors, local areas of hypoxia or acidosis and host-dependent resistance mechanisms which can cause high false-positive prediction of in vitro chemo-sensitivity. See Kern D H, Tumor Chemosensitivity and Chemoresistance Assays, Cancer, 79:7, 1447-1450, 1997.
  • Others have proposed alternative methods such as Single Photon Emission Tomography (SPECT) and Positron Emission Tomography (PET), which have been found to be useful for obtaining functional data of tumors when radiopharmaceuticals are utilized. There are several approaches for the assessment of chemotherapeutic effects that include measurement of tumor metabolism, quantification of pharmacokinetics of radiolabeled drugs and evaluation of multidrug resistance. A commonly used positron emitting radiopharmaceutical for oncological studies is F-18-Fluordeoxyglucose (FDG). FDG is a tracer, which parallels the transport and phosphorylation of glucose into the cell but is then trapped. Therefore, it is used as an estimate for the regional tumor glucose metabolism. In addition, FDG is a tracer that shows a preferential accumulation in most of the tumor types. As a result, therapy monitoring may be performed using multiple follow-up PET studies where a decrease in tumor uptake correlates with clinical response to therapy, and conversely an increase is indicative of tumor growth. PET can typically be utilized to measure the kinetics of the drug over a target area in normal tissue and in the vascular system. Generally stated, only 5FU (5-Fluorouracil) has been found useful for routine PET scanning. See Kissel et al., Noninvasive determination of the arterial input function of an anticancer drug from dynamic PET scans using the population approach, Med Phys April 1999; 26(4):609-15.
  • In operation, the PET methodology may allow for the direct measurement of radiotracer concentrations and, thus, a quantification of the 5-[F-18]FU accumulation. Dimitrakopoulou et al., Studies with Positron Emission Tomography After Systemic Administration of Fluorine-18-Uracil in Patients with Liver Metastases from Colorectal Carcinoma, J Nucl Med, July 1993, 34:1075-1081. When utilized to assess liver metastasis from the colon, kinetic data showed different distribution patterns for the metastases, the normal liver parenchyma and the vessels. The normal liver parenchyma has the highest 5-[F-18]FU uptake about 30 minutes after onset of the infusion of the tracer, followed by a decrease to 25% of the maximum at the end of the acquisition time. The uptake in the metastases was low and relatively constant during the 120-minute acquisition time. The mean uptake was one-third of the liver uptake at the same time interval. Two caveats associated with the distribution pattern reflect the difficulty in utilizing one (single) observation in determining effective therapeutic response. It was observed that the early 5-FU uptake is primarily determined by the intracellular uptake of non-metabolized 5-FU. Late 5-[F-18]FU uptake values, e.g., 120 minutes after onset of the 5-FU application, are used as a prognostic parameter for therapy response, since the data obtained from that time interval are most likely to mirror the therapeutically active fraction of the drug. In addition, 5-[F-18]FU studies demonstrated a great variability of drug uptake in liver metastases even in the same patient, which may explain the low response rates and the variability in response to therapy. The 5-[F-18]FU concentration as measured with PET prior to onset of 5-FU chemotherapy is predictive of therapy outcome, since only a high 5-FU trapping in the metastasis is correlated with regression, while low 5-FU concentration are not capable of preventing tumor growth during chemotherapy.
  • PET can also be used to study mechanisms of drug resistance by employing a combination of O-15 labeled water and 5-[F-18]FU. The former has been used to study the transport system and identified a difference between a passive and active energy-dependent transport systems. Enhanced 5-FU trapping was noted in 70% of these lesions. Since only tumor lesions with an energy-dependent transport system of 5-FU are likely to respond to 5-FU therapy, this information is believed to be of clinical value for the individualization of the therapeutic protocol. PET can be used to select those patients with metastases possessing an active 5-FU transport system, which can aid the oncologist to direct therapy by modifying the treatment protocol.
  • Multidrug resistance (MDR) occurs when cells appear to overcome the cytotoxic effect of chemotherapy. Cytotoxic drugs are rapidly eliminated, especially in cells with a high concentration of P-glycoprotein (Pgp), a transmembrane drug flux. Tumors from the colon, kidney, liver and pancreas frequently express the Pgp at high levels. Studies by Piwnica-Worms et al. reported on the use of Tc-99m-sestamibi, a synthetic organotechnetium complex, that can act both as a substrate for Pgp and can act as a marker for the expression of Pgp. See Piwnica-Worms et al., Functional Imaging of Multidrug-resistant P-Glycoprotein with an Organotechnetium Complex, Cancer Res 53, 977-984, 1993. A high Sestamibi accumulation in the tumor correlated with a low Pgp expression and a good prognosis for chemotherapy. Despite these advances and observations, there are limitations of PET methodology. Practically speaking, this evaluation method would potentially be available to only a limited number of patients since it can be time consuming, expensive and impractical for application, not only to every patient, but on multiple occasions. Secondly, PET scans cannot discriminate metabolites. In order to improve the interpretation of the PET data, Nuclear Magnetic Resonance Spectroscopy (NMRS) has also been used in some patients.
  • Following the observation in 1984 by Stevens et al., 5-Flourouracil metabolism monitored in vivo by 19 F NMR, Br J Cancer 1984, 50:113-117, who showed that 19F-NMRS could detect 5-FU in the liver of mice, the work was extended to observations in the tumors of rats and mice. See Wolf et al., Tumor trapping of 5-fluorouracil: In vivo 19 F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits, Proc Natl Acad Sci USA, January 1990, 87:492-496. In 1990, Presant et al. reported their initial observations on the clinical experience with NMRS in 11 patients. They described a “trapped” pool of intra-tumoral 5-FU, defined as a pool of 5-FU whose disappearance half-life (T1/2) is longer than its T1/2 in peripheral blood. They also presented information on the correlation between the T1/2 of 5-FU in tumors and anti-tumor response to 5-FU. Generally stated, they found that the six patients with T1/2 of greater than 20 minutes responded to chemotherapy and that the converse was also true. More recently, Presant et. al., in Enhancement of Fluorouracil Uptake in Human Colorectal and Gastric Cancers by Interferon or by High-Dose Methotrexate: An In Vivo Human Study Using Noninvasive 19 F-Magnetic Resonance Spectroscopy, J Clin Oncol 18:255-261; 2000, reported that the in vivo modulation of the tumoral pharmacokinetics of 5-FU could be measured non-invasively by 19F-MRS and suggested that such information correlates with subsequent clinical outcomes. Further, they suggested that interferon (IFNa-2a) and high-dose methotrexate could increase the intratumoral 5-FU in some patients.
  • 31P/NMR spectra contain peaks from nucleoside triphosphates (NTP), phosphocreatine (PCr), and inorganic phosphates (Pi) and can therefore provide information about tumor energy status. The potential of 31P/NMR spectroscopy for evaluating the effect of treatment (radiation and hyperthermia) on sarcomas has been studied by Dewhirst et al. Dewhirst et al., Soft-Tissue Sarcomas: MR Imaging and MR Spectroscopy for Prognosis and Therapy Monitoring, Radiology 174:847-853, 1990. They purportedly observed a relationship between treatment-induced decrease in ATP/Pi with the probability of development of necrosis and in a related study showed an increase in oxygenation after treatment correlated with the amount of tumor necrosis. Another example of an application of 31P/NMR spectroscopy is in the monitoring of biochemical inhibition of specific metabolic pathways. This inhibition is designed to enhance tumor response to radiation and chemotherapy. Agents such as 2-deoxyglucose, lonidamine, 6-aminonicotinamide (6AN) can inhibit biochemical pathways and enhance responses to chemotherapy and radiation. Koutcher et al. (in Koutcher et al., Potentiation of a Three Drug Chemotherapy Regimen by Radiation, Cancer Res 53:3518-3523, 1993) observed changes in spectra of mammary carcinoma before and after treatment with a 3-drug combination. The observed changes were used to determine the timing between the drugs and radiation based on when tumor metabolism was maximally inhibited. While the drugs alone induced no complete responses and radiation only induced a single ( 1/20) “complete response” (CR), the combination of the drugs and radiation (administered when the NMR data demonstrated maximal metabolic inhibition) yielded a 65% CR rate and a 25% durable (<1 year) CR rate, without further treatment.
  • Several groups have proposed the use of intraoperative radiation probes for the purpose of identifying cancerous regions in the body. See e.g., Zanzonico et al., The intraoperative gamma probe: basic principles and choices available, Semin Nucl Med 30 (1), pp. 33-48 (January 2000); Barber et al., Comparison of NaI(T1), CdTe, and HgI2 surgical probes: physical characterization, Med. Phys.; 18(3), pp. 373-381 (May-June 1991); and Hoffman et al., Intraoperative probes and imaging probes, Eur Jnl. Nucl. Med. 26(8), pp. 913-935 (August 1999). These techniques can be characterized as belonging to one of two primary applications: radioimmunoguided surgery (RIGS) and sentinel node detection. It is believed that the RIGS applications may be generally described as radiolabeling an antibody specific to a target tumor and then probing in the operational field with a radiation detector to evaluate which tissue may be suspect. It is believed that this technique can provide better localization than is available with SPECT (Single Photon Emission Computed Tomography).
  • The sentinel node detection techniques can be described as using an injection of a radiolabeled substance into a tumor and then recording or evaluating the “downstream” activity of the radiolabeled substance to determine the degree of lymph node involvement. A clinician can use a pen-like gamma probe to trace or detect the signal associated with the radioactivity of the lymph nodes (such as during a surgical procedure).
  • It is also known that there are changes in glycolysis in normal versus tumor cells. The facilitative glucose transporters (GLUT 1-5 and 7) have been reported as proteins that regulate transport of glucose from the blood to cytoplasm. These proteins are passive transporters and, thus, provide glucose to the interior of a cell if a concentration gradient exists. As previously suggested, increased uptake of glucose by cancer cells may be due to an up-regulation of the GLUT genes responsible for the proteins. Because transport of glucose by these transmembrane proteins is passive, the concentration in the cytoplasm is kept below the level in the interstitial fluid. This means that glycolysis can accelerate to keep up with the process and to attempt to maintain the desired internal cell level or transmembrane concentration gradient. Therapies that disrupt a key element of glycolysis may arrest the avid uptake of glucose by tumors by reducing the transmembrane concentration gradient. [18F]FDG has been used recently to look at alterations in glucose uptake following radiation therapy. This observation may be important in assessing the onset of apoptosis due to radiation exposure. Glucose transport has been studied after induction of apoptosis by gene therapy designed for a rat tumor model. [11C]glucose labeled in the 1 and 6 carbon positions was used to look at the “pentose cycle.” This cycle preferentially selects carbon in the first position and incorporates it into CO2. Thus, it has been proposed that the ratio of C1/C6 could be predictive of the staging of gliomas. However, this proposed evaluation method may be difficult in that there is a low (approximately 5%) amount of glucose entering the pentose cycle and because the evaluation method is performed in successive runs (first for C1 and then for C6) with a clinically challenging PET isotope.
  • Despite the foregoing, there remains a need to provide cost-effective and/or alternative methods, systems and devices that can individualize and customize therapy to improve response and outcome and/or otherwise monitor therapeutic response or delivery of radiolabeled agents in the body. There is also a need for methods, systems and devices that can provide increased information on normal and/or tumor glycosis and/or the impact of therapies on same.
  • SUMMARY OF THE INVENTION
  • The present invention provides methods, systems, devices and computer program products for in vivo dynamic monitoring of detected radiation which is emitted from localized tissue in a target region of the body over a selected response or watch period. Generally described, the monitoring can be carried out as a general metabolic assessment, to evaluate or monitor therapy types (including antibody and pharmaceutical therapies) and/or to obtain data and evaluate metabolic, biokinetic parameters, or predictor variables associated with the in vivo detected radiation. The data can be used, inter alia, to: (a) predict or assess the likelihood that a planned treatment will be effective (before or after a first or subsequent therapeutic dose is actually administered to the subject); (b) identify which drug or drugs will provide a suitable clinical response for that subject; (c) monitor intratumoral kinetics; (d) study pharmacokinetics and/or pharmacodynamics; (e) study the impact of modifying agents, treatments, or procedures on drug or antibody uptake and/or retention or tumor kill or morbidity; (f) measure uptake, trapping, or retention of radiolabeled analytes (for any desired treatment, whether drug, antibody, and/or radioimmunology); (g) study an individual's bio-response to a therapy; (h) exclude certain therapy choices; and (i) to evaluate metabolic activity or behavior.
  • Operations of certain embodiments can be carried out to assess glycolysis and/or to examine specific therapies with respect to altered glycolysis or dynamic changes in glycolysis. Such analysis may be carried out by employing [14C]glucose and/or glucose derivatives as well as the resulting constituents resulting from the glycolysis or metabolic biochemical process in the body.
  • Alternatively, the monitoring may be used to quantitatively measure the radiation dose received at localized tissue in the target region (such as used for radioimmunotherapy). While in other embodiments, the present invention can use the detected radiation to analyze the pharmacokinetics/pharmacodynamics or in vivo performance of certain pharmaceutical grade drugs or drug products or derivatives thereof, as well as analytes, antibodies, metabolites or other therapeutic treatments in the body.
  • Advantageously, in certain embodiments, the present invention can provide cost-effective minimally invasive methods, systems, and devices that can evaluate, in substantially real-time, one or more selected biokinetic parameters or predictor variables of a subject. Certain embodiments of the devices and systems can be configured to identify the differences in response between normal and malignant tissue and/or the differences in the physiology and biology of individual tumors (or the same at different times) and to utilize the identified information regarding same to develop individualized treatment decisions, and/or to predict therapeutic outcome or to improve tumor response.
  • Other embodiments may allow improved individualized treatment protocols based on an in vivo detected uptake or trapping or other desired response (over a selected time) of a non-therapeutic dose of a drug typically evaluated before and proximate in time to the delivery of the therapeutic dose) to predict the response of the subject to a therapeutic dose of a drug in advance of administration thereof. Such pre-delivery assessment capability may be able to allow an improved selection of chemical or treatment drug, reducing unnecessary ineffective administration of cytotoxic agents which are unlikely to be clinically effective. Thus, the present invention can identify, by measuring detected radiation associated with the uptake and retention of a radiolabeled or radioactive substance, the sensitivity or receptiveness of a tumor for a particular treatment, proximate in time to the planned delivery or administration of same.
  • Other embodiments gather data during a treatment cycle and evaluate it to determine the likely clinical efficacy based on the detected kinetic activity data.
  • Certain embodiments of the present invention are directed to methods for determining the in vivo clinical efficacy of a treatment in a subject. The method can include the steps of: (a) positioning a sensor in tissue in a region of interest in the body; (b) administering a radiolabeled analyte to a subject; (c) detecting in vivo from the implanted sensor a signal corresponding to the radiation emitted from the radiolabeled analyte in the region of interest in the subject; (d) relaying the signal to a location external of the subject's body; and (e) monitoring the (relayed) signal over time to determine the response of the subject to the administered analyte to predict or assess at least one of the in vivo clinical efficacy of a selected treatment and/or the metabolic activity in the region of interest.
  • In certain embodiments, the radiolabeled analyte may be a C-14 (beta emitter) labeled version of a non-labeled corresponding drug or antibody that is undergoing pharmacokinetic/pharmacodynamic evaluation in clinical or pre-clinical drug trials (or other drug development testing). In other embodiments, the radiolabeled analtye may be an analog of a chemotherapeutic agent for cytotoxic cancer treatment such as, but not limited to, a C-14 labeled chemotherapeutic or cytotoxic agent.
  • Certain embodiments of the present invention are directed to methods for determining the clinical efficacy or the metabolic behavior of the subject when exposed to a selected pharmaceutical or chemical product in a subject. The method comprises the steps of: (a) administering a first quantity of a C-14 radiolabeled version of a pharmaceutical product (such as a drug or antibody) to a subject; (b) detecting a signal from an in situ sensor, the signal corresponding to the radiation emitted by the radiolabeled pharmaceutical product in a region of interest in the subject; (c) relaying the signal to a location external of the subject's body; (d) repeating said detecting and relaying steps over at least about 0.25-12 hours; and (e) monitoring the signals over time.
  • In certain embodiments, the monitoring step can be used to determine the metabolic and/or biokinetic response of the subject to thereby predict or assess the in vivo clinical efficacy or local tissue sensitivity to a therapeutic dose of a pharmaceutical product prior to administration thereof.
  • The administrating step can be carried out in vivo and performed such that the radiolabeled pharmaceutical product is either delivered locally to the region of interest (such as via injection thereat) or such that the radiolabeled pharmaceutical product is delivered systemically (such as through a syringe or an intravenous catheter). The C-14 pharmaceutical can be provided as a first quantity amount which is less than a therapeutic quantity of a corresponding non-radiolabeled pharmaceutical product.
  • Other embodiments of the present invention are directed to a detection system for detecting radiation emitted from an internally administered radioanalyte. The system includes at least one radiation sensor configured for in vivo operation. The sensor is configured to detect beta radiation emitted from the radiolabeled analyte or its biochemical constituents, in or proximate targeted localized tissue in the body. The sensor is configured to detect emitted beta radiation, at least intermittently, over a period of time extending from about 0.25-24 hours (the evaluation period can be proximate in time to and at least before each of a plurality of planned therapeutic treatments which are administered temporally separate from each other). The system also includes a processor operably associated with (each of) the radiation sensor(s). The processor is configured to receive signal data associated with the detected radiation from the sensor. The processor includes computer program code for monitoring selected in vivo parameters associated with time-dependent measurement profile and/or the uptake and/or retention of the radioactive substance in the targeted localized tissue.
  • Yet other embodiments of the present invention are directed to computer program products for evaluating an individual's response to a planned cancer treatment regimen, the computer program product comprising a computer readable storage medium having computer readable program code embodied in the medium. The computer-readable program code comprising: (a) computer readable program code for receiving a first measurement of radiation detected in vivo in tissue located about a local targeted site in the body of a subject, the detected radiation corresponding to radiation emitted from a radioactive or radiolabeled substance administered internally to the subject; (b) computer readable program code for receiving a second measurement of the radiation detected in the tissue located about the targeted site after the first measurement the detected radiation corresponding to radiation emitted from the radioactive substance or radiolabeled analyte administered internally to the subject; and (c) computer readable program code for generating a time-dependent measurement profile for evaluating selected parameters associated with at least one of the uptake and retention of the radioactive or radiolabeled analyte in the localized tissue of the subject based on the first and second measurements.
  • In other embodiments, the computer program code can be configured to obtain third and fourth measurements (or more measurements).
  • Other embodiments are directed to computer program products and methods for quantifying the amount of radiation delivered to tissue in a targeted local site in the body of a subject in response to a radioimmunology treatment. The program product can include computer readable program code for (a) receiving data associated with radiation detected in vivo in tissue located about a local targeted site in the body of a subject, (b) computer readable program code for generating a time-dependent measurement profile of the detected radiation at the local site; and (c) computer readable program code for evaluating the amount of radiation delivered to the localized tissue based on the time-dependent measurements.
  • The detected radiation can be based on internally administered radiation that is directed as a therapeutic pharmaceutical treatment to a target region of interest in the subject. The computer program product can include computer program code for initiating the first and second measurements a plurality of times over an active treatment period extending at least from about 5-10 minutes to 24 hours or more, over one or a plurality treatments (such as a plurality of radioimmunology treatment sessions for the treatment of cancerous tumors or tissue).
  • The detected radiation can be used to confirm delivery of the product to the targeted site and/or to quantify dose or uptake/retention or response of the tumor to the product thereat. Such information may be used for monitoring a selected therapeutic treatment(s). The system or program can be configured to detect radiation related to the internal activity of C-14 labeled glucose. This data or information may also be used for therapeutic assessment and/or monitoring.
  • Other systems or computer programs can be configured for evaluating an individual's metabolic activity using an in vivo administered beta radiolabeled analtye or metabolite. The program includes: (a) computer readable program code for receiving data for a first measurement of radiation detected in vivo in tissue located about a local targeted site in the body of a subject, the detected radiation corresponding to radiation associated with a radiolabeled analyte administered internally to a subject; (b) computer readable program code for receiving data for a second measurement of the radiation detected in the tissue located about the targeted site after the first measurement, the detected radiation corresponding to radiation associated with the radiolabeled analyte administered internally to the subject; and (c) computer readable program code for monitoring the received data over time to evaluate the metabolic activity of the local targeted site.
  • Other embodiments are directed to a method of quantifying the amount of radiation delivered to or the metabolic activity of tissue in a targeted local site in the body of a subject. The method comprises the steps of: repeatedly detecting radiation in vivo in tissue located about a local targeted site in the body of a subject over a response window; and evaluating the uptake and retention of radiation in the local site over the response window to determine the amount of radiation delivered to the localized tissue based on the detecting step.
  • Additional embodiments are directed to systems for analyzing in vivo metabolic activity of a subject. The system includes detection means for detecting metabolic kinetic activity in vivo based on the levels of radiation present in a localized in vivo region of interest responsive to an internally administered radioanalyte in the subject over a desired time interval of interest; and analyzing means for analyzing data associated with the detected radiation to determine the in vivo metabolic kinetic activity of the subject.
  • The system may further include a biocompatible radiolabeled analyte configured for human or animal administration and the detection means can be adapted to detect the concentration activity of the radiolabeled analyte in the region of interest.
  • The present invention can acquire data associated with the detected radiation and generate at least one time-dependent measurement profile of the radioactivity in a localized region of the subject. The time-dependent profile can be analyzed to identify or quantify one or more predictor variables which captures desired information corresponding to one or more of the efficacy, performance, activity, or status of the radiolabeled substance in the body and/or targeted or localized tissue. The predictor variables or parameters can include (but are not limited to) the biological ½ life of the radiolabeled analyte in the localized tissue, the amount of time the detected radiation is above a predetermined threshold level, the amount of time that the radiation detected is increasing, the peak value of the detected radiation, the time at which the peak radiation level occurs, and the decay rate of the detected radiation.
  • The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a block diagram of a method of operation according to embodiments of the present invention.
  • FIG. 2A is a block diagram of another method of operation according to embodiments of the present invention.
  • FIG. 2B is a block diagram of an additional method of operation according to embodiments of the present invention.
  • FIG. 2C is an example of a glucose chemical structure that may be radiolabeled according to embodiments of the present invention.
  • FIG. 2D is a block diagram of another method of operation according to embodiments of the present invention.
  • FIG. 3 is a block diagram of an additional method of physiologic or biologic evaluation according to embodiments of the present invention.
  • FIG. 4A is a schematic illustration of a system employing a wireless sensor according to embodiments of the present invention.
  • FIG. 4B is a schematic illustration of a system similar to that shown in FIG. 4A but with an alternate sensor/system configuration (wired) according to embodiments of the present invention.
  • FIG. 5A is a schematic illustration of a radiation sensor located in vivo and associated monitoring system according to embodiments of the present invention.
  • FIG. 5B is a schematic illustration of a detection system according to the present invention that can be configured as a transcutaneous, intralumen or intracavity catheter or probe-based sensor.
  • FIGS. 6A-6E are graphs of simulated or predicted radiation activity measurements over time or time-dependent measurement profiles which can be monitored according to embodiments of the present invention. FIGS. 6A and 6C illustrate time dependent measurement profiles with examples of some predictor variables or kinetic parameters. FIG. 6B illustrates that the dose can be based on a mathematical integral of the area under the curve of the measurement profile. FIG. 6E illustrates that a first derivative of count per second can be mathematically derived for dose evaluation. FIG. 6D illustrates that a plurality of time-dependent profiles can be obtained on the localized tissue at different time or evaluation periods to obtain substantially real time or dynamic information so as to assess the status or receptiveness/sensitivity or performance of the drug at the localized tissue.
  • FIG. 6F is a flow diagram of a method for using calculated kinetic factors or one or more predictive variables to determine whether a biokinetic response is favorable in making therapeutic treatment decisions according to embodiments of the present invention.
  • FIG. 7 is a cross-sectional view of an implantable radiation sensor according to embodiments of the present invention.
  • FIG. 8A is a partial cross-sectional view of an alternate embodiment of a radiation sensor according to the present invention.
  • FIG. 8B is a partial cross-sectional view of an additional embodiment of a radiation sensor according to the present invention.
  • FIG. 9A is a schematic illustration of a sensor with a plurality of radiation sensing probes according to embodiments of the present invention.
  • FIG. 9B is a schematic illustration of a sensor with a plurality of fiber optic leads used to relay light according to embodiments of the present invention.
  • FIG. 10A is a schematic of a fiber optic system used to evaluate beta spectroscopy signals according to embodiments of the present invention.
  • FIG. 10B is a schematic of an implantable wireless system used to obtain data associated with internally administered beta radiation.
  • FIG. 10C is a greatly enlarged front view of an implantable wireless sensor configured to detect internally administered beta radiation according to embodiments of the present invention.
  • FIG. 11A is a graph of an exemplary in vivo response profile of the concentration or uptake over time of a radiolabeled analyte according to embodiments of the present invention.
  • FIG. 11B is a graph of another exemplary in vivo response profile of the concentration or uptake over time of a radiolabeled analyte according to embodiments of the present invention.
  • FIG. 11C is a graph of a statistical model of predicted values compared to observed results of the flank/inguinal probe region of FIG. 11B according to embodiments of the present invention.
  • FIG. 11D is a graph of additional exemplary in vivo response profiles of the counts over time of a radiolabeled analyte according to embodiments of the present invention.
  • FIG. 12A is a graph of another exemplary in vivo response profile of the concentration or uptake over time of a radiolabeled analyte according to embodiments of the present invention.
  • FIG. 12B is a graph of an additional exemplary in vivo response profile of the concentration or uptake over time of a radiolabeled analyte according to embodiments of the present invention.
  • DESCRIPTION OF EMBODIMENTS OF THE INVENTION
  • The present invention will now be described more fully hereinafter with reference to the accompanying figures, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Like numbers refer to like elements throughout. Layers may be exaggerated for clarity. In the figures, broken lines, unless stated otherwise, represent optional steps or features.
  • As will be appreciated by one of skill in the art, the present invention may be embodied as a method, data processing system, or computer program product. Accordingly, the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects. Furthermore, the present invention may take the form of a computer program product on a computer-usable storage medium having computer-usable program code means embodied in the medium. Any suitable computer readable medium may be utilized including hard disks, CD-ROMs, optical storage devices, a transmission media such as those supporting the Internet or an intranet, or magnetic storage devices.
  • Computer program code for carrying out operations of the present invention may be written in an object oriented programming language such as Java®, Smalltalk or C++. However, the computer program code for carrying out operations of the present invention may also be written in conventional procedural programming languages, such as the “C” programming language. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer. In the latter scenario, the remote computer may be connected to the user's computer through a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
  • The present invention is described below with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions specified in the flowchart and/or block diagram block or blocks.
  • These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the flowchart and/or block diagram block or blocks.
  • The computer program instructions may also be loaded onto a computer, processor (such as a digital signal processor), or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart and/or block diagram block or blocks.
  • Generally described, in certain embodiments, the proposed device and systems can be used to obtain data and/or measure or monitor the emission of radiation from radiolabeled analytes. The term “radiolabeled analytes” includes, but is not limited to, radiolabeled antibodies, radiolabeled antigens, radiolabeled nucleic or amino acids, other radiolabeled endogenous substances or molecules such as glucose or other naturally occurring substances and/or their derivatives, metabolites, or constituents, and radiolabeled exogenous substances and/or molecules such as pharmaceutical drugs or derivatives thereof, and the like, as well as combinations of the above. The emitted radiation from the radiolabeled analyte(s) can be detected in vivo from tissue in target or localized region(s) in the body. This detected and monitored radiation can provide information on one or more of the metabolic activity in the localized region, tissue, or cells, the pharmacokinetics/pharmacodynamics of a corresponding non-radiolabeled analyte or substance, the likelihood of the uptake and the retention of certain chemotherapeutic drugs in the localized region or tissue, and/or a substantially real-time or kinetic analysis of the biological status or metabolism and/or proliferation of malignant and/or normal cells in the localized tissue or region at desired points in time. The radiolabeled version of the non-radiolabeled analyte can be formulated to have the same or substantially similar pharmacological or biochemical activity as the parent analyte.
  • Such systems and methods can be used to obtain and/or analyze data or physical quantities from the living body to provide intermediate data that may be provided to a clinician or researcher for further consideration. The detection can be carried out at multiple sites about a region of interest or at a plurality of different spaced apart sites in the body. The systems, methods, and operations of the present invention may be carried out to monitor for longer times over conventional systems, the biological or physiological impact of a selected therapy (or combinations of therapies) on a target disease, disorder, or condition of the body (pharmacodynamics) in addition to the in vivo levels, activity, retention, uptake, delivery, etc., of one (or more) therapeutic agents (pharmacokinetics).
  • Certain embodiments of the systems and methods of the present invention may be used with any analyte which can be radiolabeled or made radioactive, including, but not limited to, as noted above, endogenous material that can be radiolabeled and re-introduced to the subject, or exogenous material. As also noted above, suitable analytes can include radiolabeled versions of nuclides, pharmaceuticals and derivatives thereof, antibodies, antigens, proteins, peptides, amino acids, nucleic acids, glucose and metabolites and derivatives thereof. The radiolabeled analyte may be a genetically engineered substance, which has a site-specific or tumor or tissue specific delivery target, a differentiation antigen, or an analyte which can be activated upon delivery to a particular region or tissue or which can otherwise be locally “activated” or targeted. The radiolabeled analyte or substance may be selected based on its presence or expression, i.e., a radiolabeled marker associated with a disease or cancer in the region or at the targeted site, such as an over or under expression of an antigen, antibody, peptide, protein, enzyme, amino acid or other endogenous analyte, or other genome or phenotype(s) criteria or behavior. Thus, it is contemplated that radioactive monitoring for dynamic amounts of the marker or antigen expression can provide valuable internal real time or dynamic information about cellular activity.
  • The term “glucose derivative” includes glucose molecules with a modified glucose chemical structure that is biocompatible and can be biochemically processed by the body. Examples of glucose derivatives include, but are not limited to, dextraglucose (D-glucose), and 2-deoxyglucose (2-DG).
  • Examples of marker or expression-based evaluation of antigens/antibodies (which may be radiolabeled) include those used in cancer evaluation and/or treatment. Examples of tumor-associated antigens of interest may include the CD-20 antigen (on B lymphocytes) for which treatment may include agents having antibodies to the CD-20 antigen and human epidermal growth factor (HER2) associated with some breast tumors. It is noted that HERCEPTIN may be radiolabeled and is currently approved for HER2 breast cancer treatment.
  • It is contemplated that other biomaterials may also be suitable to carry out operations of the present invention. Examples of potentially suitable biomaterials may include, but are not limited to, mixed cultures containing tumor cells and blood-derived lymphocytes (which may be from the patient him or herself) to produce cytolytic T lymphocytes (CTL) (or CTL clones or autologous CTL), that lyse the autologous tumor cells (which may be used in connection with melanoma, renal, bladder, head and neck carcinomas, non-small lung cancer, and the like). Other potential antigens/antibodies of interest include MAGE-1, MAGE-3, BAGE, GAGE-1, and GAGE-3. See, e.g., UCL Christian de Duve Institute of Cellular Pathology, Ludwig Institute For Cancer Research, URL www.Icp.ucl.ac.be/report95/licr95.html.
  • In any event, the radiolabeled analyte may be combined with other substances and formulated for the desired delivery (injection, intraveneous, subcutaneous, etc. . . . ) to produce the desired composition and/or bolus. In certain embodiments, the analyte can be formulated into a liquid solution. The solution can be formulated to dilute the concentration of the radiolabeled constituent or ingredient or to provide other desired biocompatible materials. Examples of suitable radiolabeled or radioactive substances will be discussed further below. The radioactive or radiation label can be gamma, alpha, or beta radiation, depending on the application.
  • The term “subject,” according to the present invention, includes subjects belonging to the animal kingdom, and are preferably mammalian subjects (e.g., humans, canines, felines, bovines, caprines, ovines, equines, rodents, porcines, and/or lagomorphs), and more preferably are human subjects.
  • In certain embodiments, the analyte is a therapeutic pharmaceutical drug or antibody that is configured to treat a selected physiologic or biologic condition, impairment, or disease. The radiolabel can be selected or formulated to be substantially transparent so that the non-radiolabeled version and the radiolabeled version of the same analyte has substantially the same biochemical activity in the body and/or the radiolabeled version does not interfere with the intended therapeutic, physiologic, or biologic reaction in the body. As such, the radiolabeled version of the analyte (or drug or antibody) can be such that the radiolabeled version biologically functions or is biochemically processed in substantially the same manner as a corresponding non-radiolabeled version. In certain embodiments, the radiolabel does not inhibit or interfere with the natural breakdown or reaction of the analyte and/or its constituents in the body.
  • The radiolabel can be a beta radiation label, wherein the beta radiation label is substantially transparent to the intended therapeutic physiologic or biologic reaction of the drug in the body. Examples of beta-emitting radioactive labels include one or more of C-14, P-32, P-33, I-131, Kr-85, Xe-133, TI-201, Ga-77, F-18, Cs-137, Ca-45, Ca-47, Co-60, Fe-59, Hg-203, Ni-63, Rb-86, Ru-106, Ag-110m, Na-22, S-35, Sr-90, Tc-99, H-3, Zn-65, Cu-64, O-15, N-13, and other positron emitters and beta particles used therapeutically.
  • In certain embodiments, the radioactive label is C-14. Carbon is widely used in drug evaluations and C-14 has a suitably long decay half-life and an acceptably short biological half-life for most drugs of interest. The C-14 label can thus be used with a wide variety of pharmaceutical products and is not limited to one particular drug or a small number of drugs, thereby allowing for a relatively wide, evaluation model or protocol for available therapeutic agents.
  • In certain particular embodiments, the radioactive label may be selected for its ability to (a) be used across a wide variety of therapeutic drugs, (b) generate sufficient signal in the localized tissue in the body to allow for dynamic and/or quantitative monitoring over a desired response window (of between at least about 5 minutes-30 minutes, and typically at least 30 minutes-1 hour), and (c) have a biocompatible biological half-life with a suitable shelf-life. This is in contrast to conventional evaluation methods, which, as discussed above, employ various radioactive substances. For example, PET-based methods use radionuclides that emit positrons. F-18 is one common radionuclide used in these types of procedures; however, fluorine containing drugs or therapeutic products are not common. Other radioactive labels may also only be useful in a limited number of drugs while others may have an unduly short half-life that, in turn, can limit the amount of data or the width of the evaluation window over which data can be taken. Still other radioactive labels may not generate sufficient concentration or signal levels to allow quantitative evaluation in the body (to generate unfavorably weak signals).
  • Turning to FIG. 1, in the embodiment shown, a subject can be undergoing treatment for a cancerous tumor. A quantity of a radiolabeled or radioactive substance (alone or combined with other ingredients or substances) is administered to the subject (Block 100). As shown, the quantity and/or radioactive intensity or concentration of the substance or analyte may be such that it acts as a pre-diagnostic test dose, rather than a therapeutic dose, which is delivered in advance of the therapeutic dose to assess or predict the clinical efficacy of a treatment prior to delivery of the treatment itself. The radiolabeled analyte or substance can be delivered either systemically, locally, or both (Block 105).
  • In certain embodiments, a small test or diagnostic dose of a radiolabeled substance or analyte such as a C-14 labeled analog of a chemotherapy drug or pharmaceutical can be administered to the subject proximate in time (and/or before) a treatment session (for which a non-radiolabeled version of the pharmaceutical can be used to therapeutically treat the cancer). As used herein, a “small” dose means a dose which is less than a therapeutic dose. The detected radiation can provide kinetic or predictive information about the likelihood of the success of the treatment and allow a potential clinician to proceed with the planned treatment, delay the treatment, exclude one or more of a treatment, or select a different pharmaceutical agent for treatment. In certain embodiments, the radiolabeled dose can be sized in an amount which is about a 0.1%-60%, and can be about 1-10% of that of a corresponding therapeutic dose.
  • In certain embodiments, the radiolabeled substance or analyte can have a concentration of about 100-500 nanocuries/cc to about 1-10 millicuries/cc (mCi/cc) (the latter typically being more suitable for direct injection at the target site). In particular embodiments, the concentration may be from between about 10 μCi (10−6 Curies) to about 1 mCi. The dose may be sized according to weight (children may receive doses in the lower portion of the range with large adults receiving doses at or above the typical range).
  • In certain embodiments, the concentration can be selected such that it corresponds to whole body doses of about 1-10 milliGray corresponding to concentrations conventionally used for nuclear medicine scans. In other embodiments, the radiolabeled analyte or substance can be systemically delivered at higher radiation concentrations where it is targeted for the target site (selective target or site specific activation formulations such as antibodies). In these embodiments, the tagging system may be designed to deliver a total dose on the magnitude of about 10-99 Grays.
  • Systemic deliveries may be made by any suitable mode such as via IV introduction into the vein of the subject. Local deliveries may be made by injections from a lumen of a syringe or via introduction through a transcutaneous catheter configured to direct the radiolabeled substance substantially directly to or proximate to a target region.
  • Turning again to FIG. 1, the radiation emitted from local tissue (such as a cancerous tumor) is detected in vivo. The detected radiation can be analyzed over a selected response period, cycle, or time (s) (Block 110). For example, a radiation sensor can be operably configured such that it is at least intermittently or periodically activated and may be continuously operated or monitored to relay information to a clinician over a time which is proximate to the administration of the radiolabeled analyte to about 24 hours later. In certain embodiments, the radiation is detected every 30 seconds to every 15 minutes during a portion of the detection cycle when the detected radiation values change from the prior reading. This shortened interval may be in the early portion of the monitored response cycle (such as in the first 10-60 minutes after initiation of the administration of the radiolabeled analyte). The activation or detection interval can be automatically extended when there is little fluctuation between incremental readings (based on an average between more than two readings or the values between two consecutive readings). The adjustment between detection intervals may be beneficial for some embodiments, which may employ wireless implantable sensors to preserve power (and extend operative life). Examples of parameters which can be monitored or analyzed will be discussed below.
  • In certain embodiments, which may be particularly suitable for continuous mode monitoring (but may also be used otherwise), the radiation levels can be detected and summed until the completion of the test or at the end of the evaluation/response window. The first derivative can be mathematically calculated or determined (to provide data on the rate of change of concentration) (FIG. 6E) or the lineshape, profile, or curve of parameters associated with the time-dependent measurements can be analyzed to yield the radiation level in the target issue over time.
  • Referring again to FIG. 1, a therapeutic treatment type or administration time can be selected based on the analyzed data associated with the detected radiation (Block 120). For example, based on the detected radiation over the response cycle, a clinician can have access to individualized information concerning the status of the bioactivity of the local tissue, the likelihood of the receptiveness to a desired therapeutic treatment, and/or the likelihood of a suitable uptake and retention of the desired therapeutic agent based on the uptake and retention of the administered radiolabeled analyte. As such, a clinician can select which particular chemotherapeutic agent (or agents) to administer to the subject at that point in time. Similar evaluations can be carried out periodically over the treatment cycle (typically 2 or more different chemotherapy administrations may be performed over a period of weeks and months). In certain embodiments, the radiolabeled analyte can be administered just proximate to (typically prior to) a planned chemotherapeutic treatment session. In certain embodiments, the therapeutic administration can be performed in less than 24-48 hours (and before any additional intentional or unintentional perturbation) from the monitored response cycle to reduce the likelihood that the bioactive nature or status of the tissue and, thus, the predicted response, will shift substantially.
  • In certain embodiments, the clinician may determine that conditions are unfavorable for a therapeutic treatment and delay or exclude the therapeutic treatment until local conditions improve (thereby reducing the introduction of cytotoxic drugs when the treatment outcome is likely to be unfavorable). As such, the data obtained may be used to evaluate whether to exclude certain potential therapies (including changing or prescribing alternative drug therapies) as it may not be indicated to be a viable treatment for that individual, or to postpone the treatment for a more favorable time.
  • As the detected radiation values can be monitored over time to determine or assess the present status (i.e., substantially real-time) of the localized tissue or evaluate the biokinetic or metabolic or activity response and/or the physiological or biological status of the local tissue, the method can be repeated at desired intervals, such as proximate in time to each therapeutic treatment over the active treatment period (Block 130). The data can be obtained several times during a desired monitoring period (such as twice, thrice, four or even more times). In certain embodiments, the kinetic data or radiation values of interest can be obtained before and after a particular treatment or active treatment session. Further, a radiolabeled analyte may be administered before and after a therapeutic treatment to facilitate the detection in vivo of localized response data. This repeat administration of a radiolabeled analyte may increase the detectability of the signal (increase the signal strength) in the body, depending on the length of the therapeutic treatment, and/or may provide data regarding the state of the tissue after administration of a therapeutic agent and/or at a desired point in time.
  • When selecting the therapeutic treatment, the clinician can consider a plurality of different pharmaceutical treatments and/or cytotoxic agents based on the evaluated condition or response of the tumor of the subject (Block 125). In addition, combination therapies can be considered to attempt to generate increased receptiveness. For example, heat or an externally generated and directed radiation dose or other combination therapy modality may be desirable to improve the tissue receptiveness. In any event, each of the chemotherapeutic treatment agents or combinations can be evaluated to select those types that align with or match the predetermined associated desired biological and/or physiological conditions (such as cell proliferation or sensitivity associated with uptake and/or retention of the radiolabeled analyte in the tissue) with that of the subject to yield increased clinical effectiveness.
  • Thus, in certain embodiments, the methods and systems may be used to determine the timing and type of treatment to administer to a subject so as to promote clinical efficacy based on a dynamic or substantially real-time understanding of the physiological or biological status of the targeted tissue. Other embodiments can evaluate the metabolic activity of the subject and/or to study pharmacokinetics/pharmacodynamics. For example, the data can be obtained and evaluated in a manner that provides information on the influence and/or impact on metabolic activity that certain therapies, activities, foods, vitamins, food supplements, or environmental exposures, may have on the target region of interest.
  • The system can be configured as a minimally invasive device that can, in certain embodiments, employ an implantable wireless or telemetric based radiation sensor. In other embodiments, the radiation sensor(s) can be a catheter or probe based device and placed transcutaneously or inserted via a cavity or lumen to the site of interest where a fiber optic (or bundle of fiber optics) acts as the sensor. Exemplary sensor and system configurations will be discussed further below.
  • FIG. 2A illustrates that, in certain embodiments, a C-14 labeled analyte can be administered to a subject (Block 200). The beta radiation emitted from local tissue in the subject responsive to the administered radiolabeled analyte can be detected in vivo from a radiation sensor positioned in situ in tissue proximate to a target site in the body. The detected radiation can be monitored at desired times in a monitoring period (typically generating a signal or over time) (Block 210). At least one of the dynamic or kinetic biophysical response or activity (including the physiological or biological condition or response or activity) of the subject or the pharmacokinetic and/or pharmacodynamic activity associated with the radiolabeled analyte can be monitored or determined or the monitored data can confirm that the radiolabeled analyte (or biochemical constituent thereof) is delivered to the intended targeted tissue in the subject (Block 220). The data from the monitoring step can be used to assess desired in vivo response or activity such as, for example, the clinical performance, biophysical response or non-response of the subject, or efficacy of a non-radiolabeled counterpart analyte (Block 221).
  • The detected radiation may also be calibrated to quantitatively measure the radiation dose received at the tissue. The calibration can be based on signal strength or radiation counts detected based on in vitro values of levels in tissue or otherwise defined by experimental or clinical evaluations to correlate the signal to the amount of radiation present in vivo.
  • In certain embodiments, the radiolabeled analyte corresponds to a radiolabeled version of a (non-radiolabeled) drug in the discovery phase of development or evaluation (such as before or during clinical or pre-clinical trials) and is administered to evaluate the pharmacokinetics and/or pharmacodynamics thereof.
  • FIG. 2B illustrates that, similar to the operations described in FIG. 2A, the radiolabeled analyte is a C-14 labeled glucose molecule, also known as [14C]glucose. The [14C]glucose can be monitored as it proceeds through a biochemical reaction and breaks into metabolic constituent components in the body. The C-14 labeled glucose molecule may include glucose molecule derivatives such as, but not limited to, 2-deoxyglucose (2-DG), dextra-glucose (D-glucose), or other radiolabeled glucose molecule derivative suitable for in vivo administration to a subject (Block 230). Data associated with the beta radiation corresponding to the [14C]glucose, and/or glucose derivatives, as well as one or more of its radiolabeled metabolic or biochemical constituents in the subject, which is emitted from targeted localized tissue, is obtained and monitored over time (Block 240). The dynamic kinetic biophysical and/or metabolic (that can include one or more of the pharmacodynamic or pharmacokinetic) response in the subject can be determined or evaluated based on the obtained data (Block 250).
  • The position of the C-14 label on the glucose molecule and/or a glucose derivative molecule can be selected based on one or more of a desired biochemical breakdown in the body, the desired residence time (longer or shorter) in the body, and/or the desired exit pathway of the C-14 radiolabel from the body. It is has been suggested that [3-14C]— and [4-14C] versions may release 14CO2 earlier in the biochemical reaction process while [1-14C]—, [2-14C]—, and [6-14C]— may release 14CO2 later in the process cycle. See, e.g., Hawkins et al., Cerebral glucose use measured with [14C] glucose labeled in the 1, 2, or 6 position, American Physiological Soc., C-170-C173 (1985)(diagramming the fate of C-14 in various positions of the carbon bonds of a glucose molecule on metabolism by glycoslysis and the tricarboxylic acid cycle). See also, Hamkens et al., PET in Clinical Oncology, pp. 55-65, Edited by Wieler et al. (Springer, Darmstadt, Germany, 2000) (discussing, describing, and comparing, the biochemical pathways of the metabolism of glucose and FDG (denotation of the essential enzymes v.i.)). The contents of these references are hereby incorporated by reference as if recited in full herein. Thus, embodiments of the present invention can selectively position the C-14 label to a desired carbon site on the glucose molecule.
  • In certain embodiments, the radiolabel on the glucose or glucose derivative molecule may be expelled from the body based on what constituent component the C-14 metabolizes into or biochemically breaks down into, so that is may be expelled either via respiration (via CO2), incorporated into the cell, and/or excreted in fluid. As noted above, selectively positioning the C-14 label on a carbon site on the glucose molecule can cause the body to release the radiolabeled constituent(s) earlier or later in the biochemical process (earlier discharge may also provide faster discharge of the radioactive component from the body). Monitoring the activity associated with the digestion or metabolized glucose may yield important information on the status of the localized tissue or tumor site. In contrast, 2-DG, is not metabolized by cells and may typically remain in the body for several hours to 1 day before it is de-phosphorylated and excreted.
  • Metabolized glucose data may be analyzed in a relative assessment or in an absolute assessment. For example, the signal data can be compared to absolute threshold data established from population norms (which may be segmented by population age or gender or disorder) or to relative data either normal or tumor data taken on the subject previously. The data can be used in a quantitative manner to establish concentration, quantity, rates (uptake and discharge), speed of the biochemical cycle, and the like.
  • In certain embodiments, two different response profiles can be generated, before and after certain therapies or temporally spaced apart in time, or with different analytes. For example, two response profiles can be taken with different radiolabeled analytes such as, but not limited to, both the [14C]glucose and the C-14 labeled 2-DG analyte. One or both types of glucose-based data analysis may be able to provide information glycolysis and/or the tricarboxylic acid cycle. Such information may indicate normal or abnormal cellular behavior. For example, the information may be used to assess when a tumor or site is aerobic (oxygen rich) or anaerobic (oxygen deficient). It is known that tumors have abnormal glucose metabolic activity. Growing tumors can digest or take-in increased amounts of glucose relative to normal tissue (i.e., are hypermetabolic). Thus, the presence of increased amounts of C-14 glucose during the biochemical process may be representative of a growing, aerobic, or active tumor. Such information may be able to be used to assess tumor receptiveness to a particular treatment such as a cytotoxic agent and/or to indicate that the target region comprises healthy tissue.
  • In certain embodiments, operations carried out according to the present invention can evaluate whether a given therapy has altered, disrupted, inhibited, or impaired, or promoted, the glycolysis biochemical process. This alteration may be identified earlier in a treatment cycle before glucose uptake is substantially altered, potentially providing earlier indications of therapeutic efficacy or influence.
  • FIG. 2C illustrates an exemplary glucose molecule. The glucose may be in an alpha-pyranose form. Of course, the glucose may also be formulated in other biocompatible forms as is known to those of skill in the art. As noted above, one or more of the carbon sites in the glucose molecule may be replaced with the C-14 tag as desired. Due to the body's ability to metabolize glucose, a plurality of serially administered and/or successive doses (separated over desired time intervals) of the radiolabeled analyte may be used to evaluate a patient's metabolic activity or tumor status. In certain particular embodiments, the C-14 label is selectively chosen for a particular carbon position, such as in positions C-1, C-2, C-3, C-4, C-6 or combinations thereof. In particular embodiments, the C-14 label can be located at C-3 or C-4 so as to promote metabolization with 14CO2 discharge earlier in the biochemical process.
  • FIG. 2D illustrates a series of operations that may be carried out to obtain data of metabolic activity according to embodiments of the present invention. As shown, radiolabeled or tagged glucose or (a biocompatible) glucose derivative is administered to a subject (Block 260). Data associated with the administered radiolabeled glucose and/or glucose derivative is obtained as the radiolabeled glucose or glucose derivative is delivered to at least one target region and is taken up in localized tissue, and/or metabolized into constituent components in the body (Block 265). The data can be monitored over time to evaluate the metabolic activity, the pharmacokinetics and/or pharmacodynamics of at least one target region (Block 270). The data may relate to the metabolic status of a tumor or its biochemical metabolic activity. In certain embodiments, data can be obtained from two different target regions, one associated with normal or non-diseased tissue and the other associated with abnormal or tumor tissue. Data of the normal versus abnormal or tumor tissue can be obtained and compared as the radiolabeled glucose and/or glucose derivative is taken-up, metabolized, processed and/or transformed, by the body into constituent chemical components to assess whether there is abnormal or altered behavior or activity in the tumor or abnormal tissue (Block 266).
  • In any event, whatever methods of operation and/or analyte selected, the data can be obtained at discrete points in time and compared to generate a relative assessment of biochemical or metabolic change, efficacy or inefficacy in response to a therapy, and the like. In other embodiments, the data can be used to generate absolute or quantification values of the metabolic activity and/or radiation level at the target site(s).
  • In certain embodiments, data can be collected from a plurality of different target sites. For example, but not limited, the data can be obtained proximate to (near, adjacent, or in) tumor tissue and proximate to (typically in) normal tissue. In addition, multiple “normal” and/or “target or abnormal” tissue sites of interest may be concurrently monitored.
  • The in vivo detected beta radiation corresponds to radiation emitted from localized tissue or regions. The detected radiation is attributed to the uptake and/or retention of the analyte at the localized tissue at a certain point in time or at certain points over time. Selected parameters associated with the detected radiation can be monitored. The selected parameters can include one or a plurality of various parameters such as the flux, rate or acceleration of change, and/or a parameter having been identified as predictive of a desired therapeutic outcome. Examples of selected parameters will be discussed further below.
  • Referring now to FIG. 3, in certain embodiments the present invention can act as a radioimmunology radiation dosimeter using quantification of measured or detected internally administered radiation via the localized sensor. To begin, a selected therapeutic treatment can be administered to the subject (Block 300). The therapeutic radiation treatment may be an internally administered or radioimmunology treatment that may include gamma, beta, or alpha radiation (Block 301). The therapeutic radiation treatment can be delivered systemically or locally as described above. The systemic delivery may also include the administration of radioactive genetically engineered substances which target a cancerous tumor or diseased or organ or tissue of interest. The radiation can be monitored by an in situ sensor that is positioned in tissue in a target site in the body. As such, the radiation proximate to the target tissue is detected in vivo, (including adjacent to or within the tissue of interest) and is monitored over a selected time period (Block 310). The therapeutic treatment can be assessed based on the monitored radiation data (Block 315). The assessment can include determining whether the tissue exhibits a change in biocellular, biokinetic, or biochemical process, or exhibits a desired response, uptake, retention, signal strength, or a non-response to the selected therapy. In radioimmunology therapies, the amount of radiation which reaches the target site (the desired treatment destination) can be quantified. That is, the radiation dose can be quantitatively evaluated based on the monitored detected values to assess or confirm that a desired (typically therapeutic) dose at the diseased or targeted tissue was received at the target site and/or that the appropriate lower dose was received away from the targeted site (Block 320).
  • The term “tissue” includes all substances in the body, e.g., an aggregation of morphologically similar cells and intercellular matter performing one or more functions in the body (such as, but not limited to, muscle, arteries, veins, vessels, tissue, bone, bone marrow, and the like) as well as serum, interstitial fluid or liquid. The liquid or fluid detection may be more typically measured with a fiber version of a detection or senor probe rather than a non-fiber version of the sensor.
  • In certain embodiments, a plurality of radiation sensors or sensing probes can be positioned about different locations in the targeted region to evaluate the distribution of the radiation dose across this region. In other embodiments, at least one radiation sensor can also be positioned in normal tissue, sensitive tissue, or adjacent the target site to monitor the amount of radiation which is delivered thereto to attempt to reduce the likelihood that radiation is overdosed in undesirable amounts to undesired locations. This information can allow clinicians to refocus, adjust, or revise the strength or type of the treatment (during or after a therapy session). For example, a number of pharmaceutical products can be formulated into a corresponding radiolabeled version, which allows for the particular pharmaceutical to be analyzed locally in its radiolabeled form. The radiolabeled version has the same or substantially similar pharmacological activity as the parent drug or compound.
  • Further, C-14 radiolabeled drugs have been used in the past to evaluate its physiologic impact on a subject during regulatory reviews to analyze metabolic byproducts. Typically, these types of studies have used a scintillating fluid with urine or fecal samples or exhaled 14CO2.
  • Examples of chemotherapeutic pharmaceutical products, which can be formulated with a C-14 tag, include antineoplastics such as alkylating agents, nitrogen mustards, nitrosureas, antibiotics, hormonal antagonists or androgens, antiandrogens, antiestrogens, estrogen/nitrogen mixtures, estrogens, gonadotroopin releasing hormones, immunomodulators, and other appropriate therapeutic agents. Other products not specifically listed may also be used as contemplated by embodiments of the present invention. Table 1 lists a few examples of products, which can be radiolabeled for cancer treatments according to the present invention.
    TABLE 1
    Agent Manufacturer
    A. Alkylating agents
     1. Myleran GlaxoSmithKline (Glaxo)
     2. Paraplatin, platinol Bristol Myers Squibb (BMS)
     3. Temodar Schering
    B. Nitrogen Mustards
     1. Alkeran Glaxo
     2. Cytoxan BMS
     3. Ifex BMS
     4. Leuderan Glaxo
    C. Nitrosureas
     1. BCNU BMS
     2. CCNU BMS
     3. Gliadel wafer Aventis
    D. Antibiotics
     1. Adriamycin Pharmacia & Upjohn
     2. Blenoxane BMS
     3. Idamycin Pharmacia & Upjohn
     4. Mithracin Bayer
     5. Mutamycin BMS
     6. Novantrone Immunex
     7. Rubex BMX
     8. Fludara Berlex
     9. FUDR Roche
    10. Thioguanine Glaxo
    11. Xeloda Roche
    E. Hormonal Antagonists
     1. Nilandron Aventis
     2. Teslac BMS
    F. Antiandrogens
     1. Casodex AstraZenaca
     2. Eulexin Shering
    G. Antiestrogens
     1. Arimedex AstraZenaca
     2. Aromasin Pharmacia
     3. Femara Novartis
     4. Nolvadex AstraZenaca
    H. Estrogen/Nitrogen mixture
     1. Emcyt Pharmacia
    I. Estrogens
     1. Estinyl Schering
    J. Gonadotroopin Releasing Hormones
     1. Lupron TAP
     2. Zoladex AstraZeneca
    K. Progestins
     1. Megace BMS
    L. Immunomodulators
     1. Ergamisol Jansen
    M. Miscellaneous
     1. Camptosar Pharmacia
     2. DTIC Bayer
     3. Etopophos BMS
     4. Gemzar Lilly
     5. Herceptin Genetech
     6. Hydrea BMS
     7. Intron A Scherling
     8. Lysodren BMS
     9. Navelbine Glaxo
    10. Oncovin Lilly
    11. Proleukin Chiron
    12. Rituxan IDEC
    13. Roferon A Roche
    14. Taxon BMS
    15. Taxotere Aventis
    16. Velban Lelly
    17. VePesid BMS
  • FIG. 4A illustrates one embodiment of a radiation detection system 10. As shown, the detection system 10 includes a radiation sensor 25 configured for in vivo wireless (telemetric) operation as it resides in a subject such that, during operation, the sensor 25 is proximate to or contacts tissue in the region of interest in the subject. The sensor 25 is operably associated with a processor 50 which can direct the activation of the sensor 25 and which can receive detected signals telemetrically transmitted from the sensor 25. The processor 50 is operably associated with computer program code or instructions 75 which analyze selected parameters associated with at least one of: (a) the uptake and/or retention of a radioactive or radiolabeled analyte and/or a radiolabeled biochemical constituent thereof in localized tissue; (b) the in vivo pharmacokinetics/pharmacodynamics of the radiolabeled analyte and/or a radiolabeled biochemical constituent thereof; and/or (c) the dose amount of radiation received at the localized tissue from an internally administered therapeutic radiation dose. Each of the selected parameters correspond to a plurality of values or measurements (such as one or more predictor variables taken from a time-dependent measurement profile) of a data signal associated with the radiation detected by the sensor 25 over a time period or periods of interest.
  • In certain embodiments, the sensor 25 is configured to be biocompatible and operable as it resides in the body for a period of at least about 1 day, and typically for at least about 1-3 weeks. In certain embodiments, the sensor 25 can reside in the body for about 1-3 months and is configured to be relatively non-invasive to the subject (so as to be biosealed to the environment, substantially non-irritating or unobstructive to the subject and/or so as to not unduly interfere with normal life activities).
  • As schematically shown in FIG. 4B, the sensor 25 can be mounted in a housing such as catheter and/or or be a fiber optic probe configured for insertion into the body and wired to an external operating system (represented by the solid lead lines drawn from the sensor to the processor). Such a system may be particularly suitable for short-term or acute positioning in the body and may be configured to collect data similar to the embodiment shown in FIG. 4A. The probe or catheter can be configured and sized to be positioned at the desired site intraoperatively, intraperitoneally (where the tumor or targeted tissue site is so located), subcutaneously, transcutaneously, or direct injection to the target site(s). In other embodiments, the catheter or probe can be guided or inserted into a cavity or natural lumen. In any event, the housing, probe or catheter is guided into the body until the sensor 25 is positioned in the desired location(s) in the body. In these embodiments, the sensor 25 may be hard-wired to (and powered by) the external system and activated by the processor 50 at desired monitoring times.
  • For certain embodiments, the system 10 may be a fiber-optic based radiation detector with the sensor probe comprising a plurality or bundle of fibers to provide intended surface areas for improved detectability. Light impeding cladding material may be placed over all but a desired tip portion of the fiber(s) to define a desired effective active detection surface area. One or more fibers (or a fiber bundle) may be employed. For example, a 2 mm fiber can be coupled directly to a channel multiplier head with about a 2.2 mm length exposed for active detection to define an effective active surface area of about 0.17 cm2. Suitable active surface areas may be in the range of between about 0.10 cm2-1 cm2. Examples of fiber optic sizes include those having a diameter between about 2 mm to about 250 μm. Other sizes may be used depending on the application and number of fibers employed. As desired, an opposing end portion can be coated with a thin layer of aluminum or light shielding material to shield it from ambient light as needed, or measurements can be obtained in a light reduced room.
  • An example of an intraoperative surgical probe is described in U.S. Pat. No. 6,076,009, the contents of which are hereby incorporated by reference as if recited in full herein. In other embodiments, the sensor 25 can be configured as a wireless or telemetric implantable sensor 25 as discussed in relation to FIG. 4A above. Examples of suitable implantable sensors as will be discussed further below.
  • FIG. 5A is a schematic illustration of other embodiments of the present invention. As shown, the sensor 25 is implanted in a subject at a desired target region in a subject so as to reside in the subject on a chronic basis for a desired period of time (typically between about 1 day-3 months). The system 10′ includes a reader 60, which may be a wireless reader configured to wirelessly or telemetrically activate or initiate the activation of and reception of signals from the sensor 25 (the signals including data corresponding to the detected radiation). Co-pending U.S. patent application Ser. No. 09/407,359 filed Sep. 29, 1999, the contents of which are hereby incorporated by reference as if recited in full herein, includes descriptions of suitable telemetric configurations and sensors. As is also shown in FIG. 5A, the radiolabeled analyte 80 can be a liquid which can be formulated for injection into the subject.
  • FIG. 5B illustrates another embodiment of the present invention. As shown, the radiolabeled analyte 80 may be formulated for systemic or direct injection, such as via syringe or IV injection. The system can include a photo multiplier tube (PMT) 154 in optical communication with the sensor 25 and an amplifier 152. The system may also include a multi-channel scaler 150 and a computer 50.
  • The present invention can acquire data associated with the detected radiation and generate at least one time-dependent measurement profile of the radioactivity in a localized region of the subject. The time-dependent profile can be analyzed to identify or quantify one or more predictor variables or parameters which capture desired information corresponding to one or more of the efficacy, performance, activity, response or status of the radiolabeled substance in the body and/the targeted or localized tissue.
  • Turning now to FIGS. 6A-6E, examples of parameters or predictor variables and time-dependent profiles which can be analyzed or monitored are illustrated. FIG. 6A illustrates that a monitored response time can be individualized such that measurements are obtained over a period during which the detected radiation is above a predetermined threshold value (the threshold value is represented by the broken line adjacent the X axis). In other embodiments, the response or monitoring period can be pre-determined (such as between about 0.1-0.25 to 1-3 hours or to 24 hours or longer). As shown, radiation is detected over a period of time (t). The time at which the radiation is above a particular value (shown as the threshold value, but it may be at a higher value) can be defined as the time during which the local tissue is able to uptake, trap or accumulate or retain the radiolabeled or radioactive analyte (ttrap). The detected radiation may have a peak at a particular time in the response cycle (tpeak). In addition, the radiation may increase during a portion of the response cycle (tinc) and decrease for a period of time thereafter (tdec). The rate of increase or decrease or time to reach the peak or the lower threshold may also be calculated based on the monitored values. Further, the acceleration or deceleration or decay rate (either an average or at particular times during the monitored period) can be established.
  • For example, the energy from C-14 decay peaks at about 55 KeV. Generally described, in the time-dependent measurement profiles, each “count” or point in the profile or curve can correspond to a pulse of charge, and the pulse of charge can be quantified using a charge sensitive detector. In certain embodiments, signal to noise ratios can be enhanced in various ways, such as by allowing for signal integration over short time windows of about 1 μs so that dark counts are reduced. In certain embodiments, the time duration of the signal pulses can be about 10 ns or less.
  • One or a combination of parameters or appropriate predictor variables can be correlated or statistically evaluated to determine the impact on clinical outcome or performance in the body. As such, the parameter is predictive of a desired performance, response or status of the localized tissue in the subject (or in other embodiments of the delivery and/or the quantification of the amount of radioactive substance actually delivered to the targeted treatment site).
  • For example, if a subject has a relatively long trapping time, such that it is able to retain the radiation above a certain level for greater times (either absolute or relative) than previously or in comparable subjects or as established in clinical data, this capability may represent a positive predictive factor. Similarly, if the decay rate is slow or the peak (or time to saturation) is reached later in the response cycle, this may also represent a positive predictive factor or that a favorable treatment response is indicated. Other examples include later uptake and a smaller decrease from a peak value after a representative time. For example, if the signal exhibits less than a predetermined percentage drop from peak or maximum radiation activity after a representative time (such as 0.25 to 1-5 hours after initiation of the administration of the radiolabeled analyte to the subject), this may represent a favorable predictive factor.
  • For monitoring based on [14C]glucose, or C-14 labeled glucose derivatives (such as dextraglucose), the biochemical processes associated with the metabolism or glycolysis of the glucose may be such that the radiolabeled component is discharged from the body in as little as 5-10 minutes from the time of administration, and the data collection may be carried out to obtain increased data points during a shorter collection time, such as, but not limited to, during the first 0.25 hours, such as during the time period extending between about time equal about 0 to about 15 minutes-1 hour post-initiation of the administration of the radiolabeled glucose/glucose derivative.
  • FIG. 6C represents monitoring of the biological half-life (T1/2). Biological half-life times greater than a predetermined time may be an additional favorable or positive predictive factor. The presence of several of the positive predictive factors may indicate a particularly reliable indication of a favorable treatment opportunity.
  • FIG. 6B illustrates that the area under the curve can be used to calculate the dose of radiation received at the targeted site. Other dose correlation or calculation means can also be employed. FIG. 6E illustrates that the signal can be monitored and mathematically integrated and then a (first) derivative mathematically taken to represent the rate of change of concentration over time associated therewith. For illustration, in the embodiment shown, the lineshape of FIG. 6E corresponds to the derivative of the profile of FIG. 6A, albeit in a unitless manner without accounting for the amplitude values. The activity corresponds to the count (C) over time (taken in small pulsed intervals as noted above). Of course, other parameters and quantification or evaluation processing methods can be used depending on the particular application and information desired.
  • FIG. 6D illustrates that the system can obtain a plurality of different data sets, each corresponding to a desired monitoring period. As shown, three different temporally separate response periods are monitored. The third response period is shown as having an increase in detected radiation as may occur when an enhanced or favorable treatment is identified. These monitoring procedures can be performed prior to each therapeutic treatment, or several times before a favorable treatment window is indicated. The monitoring can also be done after steps are taken to influence or induce the targeted region to be more receptive to drug uptake (such as by directing external radiation at the target site).
  • It is noted that relative or absolute values of the detected signal can be used to assess the intensity or quantify the amount of radiation at the site (such as by taking a measurement before radiation is introduced to have a baseline indication to cancel out background information or by using the ratio of two measurements).
  • FIG. 6F is a flow diagram of a method (preferably carried out by a computer program) for using at least one predictor variable taken from a time-dependent measurement profile associated with the uptake and/or retention of radiation in the tissue. The predictor variable can be a plurality of calculated kinetic factors to determine whether a biokinetic response (which can mean changes in the biological or physiological function of the subject) is favorable in order to make therapeutic treatment decisions according to embodiments of the present invention. As shown, at least one predictor variable (which can be a plurality of predictive kinetic factors) associated with the uptake and/or retention of radiation is determined (Block 300). The predictive variable can be one of those described above or other parameters. The method then assesses the metabolic activity of the subject (Block 305) and/or whether the biokinetic response of the subject is favorable (Block 310). If so, in certain embodiments then a desired treatment can be delivered to the subject (Block 320). If not, then a treatment can be delayed or postponed or altered (Block 330) to attempt to increase the chances for a favorable therapeutic response. The method may also consider the available therapy types and select one which is more likely to achieve a clinically satisfactory outcome based on tumor type, certain kinetic or activity based predictive factors, or other patient information (such as age, treatment number (such as whether it is a primary or secondary or tertiary treatment)) or the like. Alternatively, or additionally, the metabolic evaluation (Block 305) can be used to study or evaluate pharmacokinetic data (Block 306) and/or to assess the efficacy of a planned or delivered therapy (Block 307).
  • The detection systems contemplated by embodiments of the present invention may be configured in several suitable configurations. For example, the system 10 can be configured: (a) as a fiber-based system with externally located operating electronics such as shown in FIG. 5B and 10A; (b) as a multiple-implantable component system such as shown in FIG. 9 (indirect detection that use optical fibers with scintillators that can feed light back to a collective photodiode) and FIG. 10B (direct beta radiation such as with a detector crystal); (c) a single implantable unit telemetry linked to an external reader such as shown in FIG. 10C (semiconductor used as a direct detector that similar to FIG. 10B can directly convert the beta into electron-hole pairs that are electrically measured); and (d) a single implantable unit with an indirect detector such as shown in FIG. 7 (the body of the implantable unit is the scintillator and is in optical communication with a photodiode). A combination of the systems or selected components described herein may also be employed. In certain embodiments, a plurality of sensing probes (direct and/or indirect) can be used with a central or single external reader to monitor radiation at more than one location in the body.
  • Generally stated, there are two primary means for measuring ionizing radiation using a solid-state detector: namely, direct and indirect conversion. As noted above, the radiation sensor 25 of embodiments of the present invention may be configured for direct or indirect detection. In direct conversion, the ionizing radiation itself creates an electron-hole pair in a region of the detector, and these changes can be separated by a biasing electric field and collected as a current through or in the device. Indirect conversion converts ionizing radiation to light in a scintillator and the light is detected by the mechanism involved in the pair production described above.
  • As such, the detection system 10 and/or the associated sensor(s) 25 may be physically and/or operationally configured in a number of suitable designs. For example, referring now to FIG. 10A, the sensor 25 of the detection system 10 may be configured for acute placement of a percutaneous or internally located scintillating fiber(s) that couples to an externally located detector 10D. That is, the sensor 25 directly relays the light signal to a detector 10D located outside the body. In the embodiment shown in FIG. 10A, the external detector 10D comprises those components inside the broken line. Other configurations of detectors 10D may be employed. This embodiment may reduce the size and electronic operational complexity of the portion of the device inserted or placed into the patient.
  • As shown in FIG. 10B, in other embodiments, a fully implantable sensor assembly 25 may be configured with at least one sensor head (probe body) 25 s that is independently positionable in the body of the subject so that it contacts the targeted tissue. The sensor or probe body 25 s is connected to a processor body 25 p via one or more fibers or wires 25 w and can be (subcutaneously) implantable a distance away from the probe body 25 s typically closer to the surface of the skin. Although illustrated as subcutaneously implanted, the processor body 25 p may also be externally mounted onto the skin of the subject and secured in position with an external biocompatible covering. The processor body 25 p can be configured to include most of the wireless transmit/receive circuitry and so that it communicates with an external reader 60. The internal processor body 25 p can include a differential receiver 25 1, an amplifier/pulse shaper 25 2, a modulator 25 3, and a loop antenna 25 4 that can be magnetically coupled to a like component in the external reader 60. The processor body 25 p can also include other components configured to power the sensor 25 s and/or communicate or interface with the external reader 60. The probe body or sensor 25 s can comprise the active sensing component such as a detector crystal 25 s1 and a charge amplifier/bias network line, driver 25 s2. The external reader 60 includes a telemetry antenna and the processor 50.
  • In still other embodiments, as shown in FIG. 10C, the sensor 25 is a unitary body that includes the active sensor, shown as a direct beta radiation detector 25 s, as well as the operational and communication electronics 25 e that is configured to wirelessly communicate with the external reader and collect the radiation data. The unitary body may be housed in a biocompatible sealed-glass or suitable material housing 25 c that is configured for direct detection of the radiation and miniaturized and implantable into the target tissue. The support electronics 25 e can be positioned on a circuit substrate 25 sub. The implantable unit 25 may also include a ferrite core to promote external communication operations. The radiation sensor 25 can be implanted in the body of a subject via surgery, injection, or inserted through a medical trochar. The radiation sensor 25 can be miniaturized such as sized at about 2-3 mm in width (or less) and about 10-20, and typically less than 25 mm in length. Each of the implantable versions shown in FIGS. 10B and 10C may be particularly suitable for chronic in vivo placement.
  • The operating power for certain of the implantable sensor 25 configurations may be provided by an inductive coupling of a RF field positioned in the vicinity of the implantable sensor 25. This is typically provided by a reader 60 (FIG. 5A) which can generate the desired power field and receive the signals from the sensor 25 (devices which include both transmit and receive functions may be termed a “transponder”). Alternatively (or additionally), the implantable sensor 25 may employ an internally mounted battery as a power source (not shown). See U.S. patent application Ser. No. 09/407,359 incorporated by reference above. In certain embodiments, the reader 60 (FIG. 5A) can be configured to transmit information as well as power to the sensor 25 (for inductively powered models) and to receive the detected radiation signals (i.e., a “two-way” system).
  • FIG. 7 illustrates an indirect conversion sensor 25. Turning now to FIG. 7, an example of an alternate implantable radiation sensor 25 is illustrated. The radiation sensor 25 can be implanted in the body of a subject via surgery or inserted through a medical trochar. As before, the radiation sensor 25 can be miniaturized, such as sized at about 2-3 mm in width (or less) and about 10-20 mm, and typically less than 25 mm in length. The radiation sensor 25 shown in FIG. 7 is configured to measure or detect ionizing radiation by generating analog or digital signals that represent the detected or measured radiation.
  • In certain embodiments, the sensor 25 can include a photodiode or similar semiconductor element as the active sensor. Examples of suitable active sensors can include, but are not limited to, a silicon photodiode operating in photovoltaic mode, a silicon photodiode operating in reverse bias mode, silicon photodiode operating in avalanche mode, an avalanche photodiode (APD), an APD in Geiger mode, a silicon PIN diode, a charge coupled device (CCD), other photodiodes or radiation sensors composed of gallium arsenide, II-a natural and CVD diamond, GaN, SiC, CdZincT (“CZT”), and ionization chambers and miniature electron multiplier and photomultiplier devices.
  • In the embodiment shown in FIG. 7, the body of the sensor 25 may be molded into a desired geometry from a scintillating material 28. In the embodiment shown, a miniaturized elongated cylindrical body 25 b is used to hold the internal circuitry. The inner and outer surfaces 25 i and 25 o of the body 25 b include a reflective material 25 r. As shown, in certain embodiments, the entire perimeter of the body of the sensor 25 is able to act as a scintillator. The reflective material 25 r may be positioned to encase the outer and inner walls of the scintillator material. The reflective material 25 r may be formed onto the scintillator material by various techniques such as vacuum deposition, coating, spraying, or the like. The reflective surfaces 25 r define the boundaries of the light guide or light channel 33 which, in operation, captures and directs the light created by the conversion of the ionizing radiation to at least one “impinging” or detection point 26 which does not have the reflective coating, which allows the light to travel out of the light channel 33 and into to at least one proximately positioned photo detector 30.
  • As shown, the sensor 25 has two opposing light input points 26, each of which is in optical communication with a respective photo detector, such as one of the photodetectors 30. The photodetector 30 resides on a circuit substrate 32 on opposing sides of a line of symmetry extending axially along the body of the device. An index matching material can be positioned between the light entrance surface of the photodiode 30 and the exit portion of the light guide 26. The index matching material may be formed onto the exit portion of the light guide 26 or maybe formed as a film or pad held therebetween. The index matching material may be selected so that its refractive index is close to the average of the indices of the scintillating material and the material forming the entrance or front surface of the photodiode 30 f (and typically such that it is substantially different from air). As noted above, for certain embodiments, the radiation sensor 25 is configured to detect peak radiation on the level of about 55 KeV. The radiation sensor may be operated to provide about 20-1000 or more counts per second. For example, for 166 nCi/cc, and about a 2 cm detector (active surface) region, the radiation sensor 25 may provide about 30 counts per second.
  • A ferrite core inductor 40 is positioned in the cavity of the sensor body 25 b away from the photodiode(s) 30. Additional support or components 35 may be mounted to the circuit substrate to provide operational or mechanical support therefor.
  • It is noted that other suitable geometries can also be used to form the light guide or channel(s) 33. FIG. 8A illustrates a single photodiode 30 located at a light exit portion 26 at one end of the light guide channel 33. FIG. 8B illustrates a light exit portion 26 at an end portion of the body of the sensor 25 b.
  • FIG. 9A illustrates that a sensor 25′ with multiple radiation probes 25 p, each on a flexible arm 25 arm can be used to detect at different regions in the desired region of the body. The radiation sensor 25′ may be implantable with the center body 25 s housing the ferrite core inductor (acting as a power/transmitting satellite body) and the end probes 25 p providing the lightguides and scintillators and being connected to the primary body. The arms of the probes 25 arm can be covered in reflective material to channel the light to selected photodiodes in the center body 25 s (the probes being configured so that they are each in optical communication with a selected photodiode therein). As noted before, the radiation sensor 25, 25′ may also be positioned on a catheter or probe. In this embodiment, the sensor(s) 25, 25′ may reside on a perimeter portion thereof such that, in position in the body, each (the active part of the probe or sensor) is exposed to the desired target region in the subject so as to allow the radiation to activate the scintillator material.
  • FIG. 9B illustrates that a sensor 25″ may also include a sensor body 25 b with a plurality of fiber optic segments or leads 125 positioned in the tumor mass.
  • The fiber optic leads 125 may be coated with a scintillator material as noted above and used to collect, capture, and relay light scintillated from different regions of the target site to the sensor body 25 b. Each lead 125 may be polled separately of the light funneled concurrently to one or more active sensing regions in the sensor body 25 b which may be configured with or in optical communication with a PMT, photo-avalanche detector or the like.
  • The present invention is explained in greater detail in the following non-limiting Examples.
  • EXAMPLES
  • A fiber optic probe suitable for transcutaneous placement was used with a photomultiplier tube for detection of beta radiation from C-14 labeled glucose (available from Amersham Pharmacia Biotech). A commercially available channel multiplier tube (from Perkin Elmer, model C943 P) was used with a small array of scintillating fibers (from Bicron). The fibers were packed loosely into a retaining collet and fixed in place with epoxy (EPO-TEK 301). The sample surface was then polished to remove any residual epoxy from the faces of the fibers. The active area of the fiber bundle was about 0.17 cm2, and typically the active surface is at least about 0.10-1 cm2. The opposite end of the fiber bundle was mated to the surface of the channel multiplier with optical cement. The system was assembled with a power supply, the channel multiplier and the fiber bundle detector.
  • The C-14 labeled glucose was used at a concentration of about 50-200 μCi/ml and the tips of the fibers were exposed to the solution in a light-tight enclosure. Current pulses from the channel multiplier due to beta events were amplified (using amplifier model A101 from Amptek) and sent as TTL pulses. A LabView device (from National Instruments) was used to record or monitor the counts per time. No pulse-height analysis was performed on the counts from the channel multiplier. About 850 counts per second were recorded whereas the background count was below about 25 counts per second.
  • The energy spectrum from C-14 decay peaks at 55 KeV. The average range of the C-14 beta in water is believed to be about 50 μm. Using the effective surface area of the fiber bundle, the count rate observed was consistent with an effective detection thickness of 50 μm. That is, the attenuation of betas reaching the fibers due to the water is equivalent to having the listed activity present in a uniform layer on the face of the fiber that is 50 μm thick.
  • The detector sensitivity can be impacted by the amount of surface area. In operation, each count corresponds to a pulse of charge and this charge can be quantified using a charge sensitive detector. The signal to noise ratio may be enhanced by allowing for signal integration over short time windows, in the range of 1-100 μs, and more typically closer to the lower end of the range so that dark counts are reduced. The time duration of the signal pulses can be less than about 10 ns.
  • For in vivo evaluations, a 2 mm fiber bundle may be inserted into position via a small incision at an entry site. A 13 gauge needle, with a solid removable component, can be inserted into the incision. The solid component can be removed and replaced with the fiber or fiber bundle. Once in place, a retention component can be applied to secure it in position (suture, surgical glue or the like) and the needle removed. The labeled glucose can be injected into the tail vein of test animals (such as rats) in a single bolus. The total activity may range from about 1-10 mCi based on the SNR noted above. After several passes in the blood stream, tissue levels of C-14 will rise (approximately 2-3 minutes after administration). The radiation detected by the fiber bundle and relayed to the photomultiplier tube can be monitored until the concentration drops to about 10% of the initial value in counts per second to evaluate individual differences in bio or pharmacokinetics between subjects and tumors.
  • Experiments using single or dual probe sensors have been used to obtain in vivo response data. The radiolabeled analytes used in the in vivo experiments included 14C-2DG (C-14 labeled 2-deoxyglucose) and 14C-5FU (C-14 labeled 5-Fluorouracil, a chemotherapeutic cytotoxic agent).
  • FIG. 11A illustrates a response profile graph (an integrated counts (above threshold) over time profile) taken over a monitored time period of about 85 minutes (study #2). The counts were taken on a thirty seconds/sample count time frame. In this experiment, a fiber optic probe was positioned subcutaneously in “normal” or non-cancerous tissue in the back of a Fisher 344 rat. A dose of 50 μCi of 14C-2DG was injected in the tail vein. The data was monitored for about 85 minutes. As shown, the counts increased after the injection as reached a plateau at about 10 minutes from the time of injection (about 35 minutes into the monitoring period). The initial portion of the graph has values that represent “baseline” or dark current. At about point “70” (corresponding to about 35 minutes), the injection is given and uptake continues until it plateaus around point “90” (corresponding to about 45 minutes).
  • FIG. 11B-11C illustrate graphs of data obtained using two probes, each placed subcutaneously in normal tissue of a 190 gram female Fisher 344 rat, one placed in the flank/inguinal and the other in the scapula (study #4). The graph plots μCi/ml over time at 90 second per mark with the upper line corresponding to the data obtained at the scapula and the lower line corresponding to the data obtained at the flank. In this experiment, a bolus of 200 μCi of 14C 2-DG was administered via intra-peritoneal (IP) injection. The data was monitored for about 96 minutes. As shown, higher concentrations were obtained in the scapula region compared to the flank region. The data supports that pharmacokinetic modeling of in vivo concentration data is feasible.
  • FIG. 11C is a graph of a pharmacokinetic model-fit of the flank normal tissue data (from the inguinal region) of FIG. 11B versus time (μCi/ml versus time in minutes). The triangulated points represent observed data and the line represents the predicted values. As shown, there is a significant ramp up in the value of the detected signal or counts during the first 10 minutes, tapering to a gradual slope uptake in the 10-30 minute range, followed by a substantial level region in the curve at about 35 minutes that extends to just over the 60 minute range, whereupon the line is predicted to taper down. The peak or maxima point in the graph is reached in the 20-50 minute range according to the observed points on the graph. FIG. 11C used a one compartmental PK model to generate the predicted data with 1st order input and 1st order elimination kinetics. This statistical model was used to model the observed values obtained from the flank/inguinal probe versus that which can be predicted using a model of the previously stated characteristics. Other statistical functions may also be used to develop a predictive model. Departures from the model may be used to evaluate tumor status such as growth, remission, or kill and/or irregular metabolic or response behavior.
  • FIG. 11D is a graph of two other studies, identified by D#2 and D#3. Each of these studies used 200 μCi of 14C-2DG administered via an IV to a 180 g rat to monitor the number of integrated counts obtained per 90 seconds in a sampling period (90 seconds per each indicated mark on the time axis). As shown, two probes were used to gather response data both in normal (D#2N, D#3N) and tumor (D#2T, D#3T) tissue.
  • FIG. 12A is a graph of a response profile of data in two locations in a tumor bearing 270 g Fisher 344 rat, obtained via a dual probe test set-up (study #5). Again, one of the two probes was positioned subcutaneously in the scapular tissue (in a tumor) and the other in the flank (normal tissue) of the rat. A dose of 250 μCi of 14C labeled 5FU was administered via intraperitoneal injection. Data was monitored for about 100 minutes. FIG. 12A is a graph of the concentration of the radiolabeled analyte (μCi) over time (minutes) and illustrates that 14C-5FU is relatively slowly absorbed into the flank tissue and scapular tumor after the injection. The concentration and uptake profiles of the 14C-5FU are similar for both locations. The uptake profile is consistent with results presented by Mahteme et al., Anti-Cancer Res, 18:943-50, 1998 (describing an autoradiographic study in the rat). As shown in FIG. 12A, the 14C concentrations continue to rise after about 90-100 minutes from the time of injection.
  • FIG. 12B is a graph of a response profile of concentration (μCi) over time (minutes) of a 120 μCi dose of 14C-5FU administered via an IV in the tail vein in a 300 gram Fisher 344 rat (study #6). Again, two probes were subcutaneously placed in the rat, one in the flank (in tumor tissue) and the other in normal tissue at the scapula. This subject was monitored about 70 minutes after injection. This graph illustrates that the 14C-5FU uptake is measurable or detectable shortly after the injection and that the concentrations peak after within about 10-30 minutes after dosing. The upper line represents the flank (tumor tissue) and the lower line represents the normal scapula tissue. Comparing the two lines in the graph, it is shown that in this experiment, the 14C concentration level peaks earlier in the tumor tissue than in the normal tissue.
  • It is anticipated that a glucose based radiolabeled analyte can be administered multiple times during a treatment period to evaluate metabolic activity and/or tumor response. In addition, a radiolabeled glucose (or other metabolite) can be administered along with a therapeutic agent (which may also be radiolabeled), typically each at different times.
  • In summary, in certain embodiments, the present invention may be used to assess metabolic response or activity and/or may help identify more favorable treatment periods or a subject's likely affinity or sensitivity to a drug before a therapeutic dose is administered. The data can be obtained in substantially real time via intermittent, episodic, or substantially continuous monitoring during desired monitoring periods to provide information on the biological, physiological, and/or metabolic behavior of one or more target regions of interest. Such data may be employed to assess (a) single or combination therapies (such as which therapy should precede the other or whether both should be delivered concurrently or proximate to the other, and the like); (b) pharmacokinetics/pharmacodynamics; (c) alterations in or status of metabolic activity or function; (d) tumor response or status; and (e) drug behavior in drug discovery programs or pre-clinical or clinical trials.
  • Unlike conventional treatments, where empirical protocols on the timing and the toxicity of the planned treatment can guide deliveries of cytotoxic agents which may be more damaging to normal tissue than to any positive treatment impact on the malignant cell population, certain embodiments of the present invention can allow for customized treatments based on the dynamic changes during treatment that occurs within a malignant cell population. Making this information available to attending physicians and clinicians can allow them to exploit the revealed differences between malignant and normal cells, and hence improve the treatment procedures to achieve better outcomes.
  • The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. In the claims, where used, means-plus-function clause are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims (30)

  1. 1. A system for detecting in vivo pharmacokinetic, pharmacodynamic and/or metabolic activity, comprising:
    at least one radiation sensor configured to detect in vivo beta radiation at least intermittently over a period of time, the at least one sensor adapted to be positioned in solid tissue, and configured to detect the beta radiation as it is emitted in response to an administered analyte as the analyte is biochemically processed by the body, wherein the analyte comprises at least one of the following: radiolabeled glucose, a radiolabeled glucose constituent, and a radiolabeled glucose derivative; and
    a processor operably associated with the at least one radiation sensor and configured to receive data associated with the detected radiation from the at least one sensor, wherein said processor is configured to electronically monitor selected in vivo parameters associated with one or more of the uptake, processing, and retention of at least one of the radiolabeled glucose, the radio labeled glucose constituent and the radiolabeled glucose derivative in the targeted localized solid tissue based on the data received from the at least one sensor.
  2. 2. A system according to claim 1, wherein the radiolabel comprises C-14 (carbon 14), and wherein the processor includes a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising computer readable program code for monitoring selected in vivo parameters associated with one or more of the uptake, processing, and retention of the C-14 labeled glucose, C-14 labeled glucose constituent or C-14 labeled derivative in the at least one targeted localized solid tissue.
  3. 3. A system according to claim 1, wherein the sensor is configured as an implantable telemetric sensor adapted for chronic implantation in solid tissue proximate a tumor site, and wherein the processor is configured to evaluate the metabolic activity of the tumor site.
  4. 4. A system according to claim 1, wherein the processor is held in a remote housing, and wherein the at least one sensor is configured to wirelessly transmit signals associated with the in vivo detected radiation to the processor over a period extending from at least about 1 week.
  5. 5. A system according to claim 4, wherein the at least one sensor is inductively powered and configured to wirelessly transmit signals to the associated processor with the in vivo detected radiation over a desired investigational period.
  6. 6. A system according to claim 1, wherein the at least one sensor is a plurality of discrete spatially separated sensors, including first and second sensors that are adapted to detect radiation emitted from respective first and second spatially separate locations in the body.
  7. 7. A system according to claim 6, wherein the first location is associated with normal or non-diseased tissue and the second location is associated with diseased, impaired, abnormal, or cancerous tissue.
  8. 8. A system according to claim 1, wherein the radiolabel comprises C-14, the system further comprising a remote reader configured to communicate with the at least one sensor, the reader comprising the processor and being configured to programmatically evaluate selected predictive variables or parameters associated with at least one of the uptake and retention of at least one of the C-14 labeled glucose, the C-14 labeled glucose constituent, and the C-14 labeled glucose derivative in the localized tissue to determine at least one of the following: the biological half life thereof, the amount of time the detected radiation is above a predetermined threshold level in the solid tissue, the amount of time that the radiation detected is increasing in the solid tissue, the peak value of the detected radiation in the solid tissue, the time at which the peak radiation level occurs in the solid tissue, and the decay rate of the detected radiation in the solid tissue.
  9. 9. A system according to claim 1, wherein the radiolabel comprises C-14, and wherein the processor is configured to determine the concentration of at least one of the C-14 labeled glucose, the C-14 labeled constituent and the C-14 labeled derivative in the at least one localized region of interest.
  10. 10. A system according to claim 1, wherein the processor is configured to determine a time-dependent profile of emitted radiation in the solid tissue.
  11. 11. A system according to claim 1, wherein the radiolabel comprises C-14, and wherein said at least one sensor is configured to detect radiation related to biochemical processing of at least one of C-14 labeled 2-deoxyglucose and a C-14 labeled constituent thereof.
  12. 12. A system according to claim 1, wherein the radiolabel comprise C-14, and wherein said at least one sensor is configured to detect radiation related to internal activity of C-14 labeled dextraglucose and a C-14 labeled constituent thereof.
  13. 13. A system according to claim 1, wherein the radiolabel comprises C-14, and wherein said sensor is configured to detect radiation related to internal activity of an administered C-14 labeled glucose or C-14 glucose derivative, wherein the C-14 labeled glucose or glucose derivative is selected to have a modified glucose molecular chemical structure that is biocompatible and can be bio-chemically processed by the body.
  14. 14. A system for analyzing an in vivo response of a subject, comprising:
    an implantable radiation detector for detecting radiation present in at least one localized solid tissue region of interest in a subject associated with internal activity of an administered quantity of an analyte comprising at least one of C-14 labeled glucose, a C-14 labeled glucose constituent, and a C-14 labeled glucose derivative, in the at least one solid tissue region of interest over a desired time interval of interest; and
    a reader in communication with the implantable detector for collecting radiation data from the detector associated with the detected radiation to determine at least one of the following: the in vivo dynamic, kinetic, and metabolic response of the subject.
  15. 15. A system according to claim 14, wherein the detector is configured to detect the concentration of the analyte in the at least one localized region of interest.
  16. 16. A system according to claim 14, wherein said detector is configured to detect radiation related to in vivo biochemical processing of C-14 labeled 2-deoxyglucose or a C-14 labeled derivative of 2-deoxyglucose.
  17. 17. A system according to claim 14, wherein said detector is configured to detect radiation related to the internal activity of at least one of C-14 labeled dextraglucose and a C-14 labeled constituent thereof
  18. 18. A system according to claim 14, wherein said detector is configured to detect radiation related to the internal activity of an administered C-14 labeled glucose derivative, wherein the C-14 labeled glucose derivative is selected to have a modified glucose molecule chemical structure that is biocompatible and can be bio-chemically processed by the body.
  19. 19. A system according to claim 14, the reader further comprising a processor having a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising computer readable program code configured to receive and analyze signals associated with the biochemical processing of at least one of the C-14 labeled glucose, the C-14 labeled glucose constituent and the C-14 labeled glucose derivative and a corresponding radiolabeled biochemical constituent thereof in the body.
  20. 20. A system according to claim 14, wherein the sensor is chronically implanted proximate a tumor treatment site, and wherein reader is configured to provide assess a likelihood of receptiveness of a tumor treatment site to a therapeutic cytotoxic treatment based on the monitored radiation data in the solid tissue proximate the tumor site.
  21. 21. A system according to claim 14, wherein the reader is configured to repetitively obtain radiation measurement data in the solid tissue in substantially real time over a desired monitoring window to evaluate changes in physiological, biological and/or metabolic behavior of a tumor treatment site.
  22. 22. A system for analyzing an in vivo response of a subject, comprising:
    a radiation detector for detecting in vivo radiation present in at least one localized solid tissue region of interest in a subject associated with internal activity of an administered quantity of C-14 labeled 2-deoxyglucose in the at least one solid tissue region of interest over a desired time interval of interest; and
    a reader in communication with the implantable detector for collecting radiation data from the detector associated with the detected radiation to determine at least one of the following: the in vivo dynamic, kinetic, and metabolic response of the subject.
  23. 23. A system according to claim 22, wherein the reader is configured to assess whether a tumor treatment site is likely to be receptive to a therapeutic cytotoxic treatment based on the monitored radiation data in the solid tissue proximate the tumor site.
  24. 24. A system according to claim 22, wherein the reader is configured to repetitively obtain radiation measurement data in substantially real time over a desired monitoring window to evaluate changes in physiological, biological and/or metabolic behavior of a tumor treatment site.
  25. 25. A system for analyzing an in vivo response of a subject, comprising:
    a radiation detector for detecting in vivo radiation present in at least one localized solid tissue region of interest in a subject associated with internal activity of an administered quantity of a C-14 labeled glucose derivative in the at least one solid tissue region of interest over a desired time interval of interest, wherein the glucose derivative is selected so that it has a modified glucose molecular chemical structure that is biocompatible and can be bio-chemically processed by the body; and
    a reader in communication with the implantable detector for receiving and analyzing radiation data from the detector associated with at least one of the C-14 labeled glucose derivative and a C-14 labeled biochemical constituent thereof to determine at least one of the following: the in vivo dynamic, kinetic, and metabolic response of the subject.
  26. 26. A system according to claim 25, and wherein the detected radiation is from solid tissue proximate a tumor site.
  27. 27. A system according to claim 25, wherein the detector and reader operate proximate in time to and before a planned therapeutic treatment.
  28. 28. A system according to claim 26, wherein the reader is configured to provide a predictive indication of a receptiveness of the tumor site to a therapeutic cytotoxic treatment based on the monitored radiation data in the solid tissue proximate the tumor site.
  29. 29. A system according to claim 25, wherein the reader is configured to repetitively obtain radiation measurement data in substantially real time over a desired monitoring window to evaluate changes in physiological, biological and/or metabolic behavior of a tumor treatment site.
  30. 30. A system for analyzing in vivo metabolic activity of a subject undergoing treatment for cancer, comprising:
    detection means for detecting metabolic activity in vivo based on levels of radiation present in localized tissue in the subject over a time interval of interest in response to administration of a radiolabled glucose or glucose derivative; and
    analyzing means for electronically analyzing the detected radiation data to determine the in vivo metabolic kinetic activity of the subject.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090018403A1 (en) * 2007-07-12 2009-01-15 Sicel Technologies, Inc. Trackable implantable sensor devices, systems, and related methods of operation
WO2010033668A1 (en) * 2008-09-19 2010-03-25 Bayer Healthcare Llc Analyte sensors, testing apparatus and manufacturing methods
US20100298679A1 (en) * 2008-02-04 2010-11-25 Bayer Healthcare Llc Semiconductor based analyte sensors and methods
US20110172559A1 (en) * 2008-09-19 2011-07-14 Bayer Healthcare Llc Lancet Analyte Sensors and Methods of Manufacturing
US20110180405A1 (en) * 2008-09-19 2011-07-28 Bayer Healthcare Llc Analyte Sensors, Systems, Testing Apparatus and Manufacturing Methods
US20110201993A1 (en) * 2009-08-19 2011-08-18 Olympus Medical Systems Corp. Detecting apparatus and medical control method
US20120241628A1 (en) * 2009-05-12 2012-09-27 Juergen Hesser Detector for the detection of ionizing radiation
WO2014143222A1 (en) * 2012-05-30 2014-09-18 Lucerno Dynamics, Llc System for the detection of gamma radiation from a radioactive analyte
WO2015121843A1 (en) * 2014-02-17 2015-08-20 Winmedical S.R.L. A device for measuring a plurality of parameters in patient subject to a treatment with radiopharmaceuticals
US9309551B2 (en) 2008-09-19 2016-04-12 Ascensia Diabetes Care Holdings Ag Electrical devices with enhanced electrochemical activity and manufacturing methods thereof
WO2017087945A1 (en) * 2015-11-20 2017-05-26 Acea Biosciences, Inc. Cell-substrate impedance monitoring of cancer cells
US9939533B2 (en) 2012-05-30 2018-04-10 Lucerno Dynamics, Llc System and method for the detection of gamma radiation from a radioactive analyte

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8489176B1 (en) 2000-08-21 2013-07-16 Spectrum Dynamics Llc Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical procedures
US9040016B2 (en) 2004-01-13 2015-05-26 Biosensors International Group, Ltd. Diagnostic kit and methods for radioimaging myocardial perfusion
US8565860B2 (en) 2000-08-21 2013-10-22 Biosensors International Group, Ltd. Radioactive emission detector equipped with a position tracking system
US8909325B2 (en) 2000-08-21 2014-12-09 Biosensors International Group, Ltd. Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical procedures
US7557353B2 (en) 2001-11-30 2009-07-07 Sicel Technologies, Inc. Single-use external dosimeters for use in radiation therapies
CA2475522A1 (en) * 2002-02-12 2003-08-21 Vistatec York Limited Method of radio-labelling biomolecules
US6891166B2 (en) * 2002-07-02 2005-05-10 Ray Therapy Imaging Ab Multi-layered radiation converter
JP2006507885A (en) * 2002-11-29 2006-03-09 ギブン イメージング リミテッド The method of in vivo diagnosis, apparatus and system
EP1594551A2 (en) * 2003-02-19 2005-11-16 Sicel Technologies, Inc. In vivo fluorescence sensors, systems, and related methods operating in conjunction with fluorescent analytes
US20040254448A1 (en) * 2003-03-24 2004-12-16 Amies Christopher Jude Active therapy redefinition
JP2007521477A (en) * 2003-06-26 2007-08-02 ギブン・イメージング・リミテツド The method for detecting in vivo apparatus, and systems
US7412280B2 (en) * 2003-07-01 2008-08-12 Ge Medical Systems Global Technology Company, Llc Systems and methods for analyzing an abnormality of an object
US9470801B2 (en) 2004-01-13 2016-10-18 Spectrum Dynamics Llc Gating with anatomically varying durations
US8423125B2 (en) 2004-11-09 2013-04-16 Spectrum Dynamics Llc Radioimaging
WO2006051531A3 (en) 2004-11-09 2006-09-28 Spectrum Dynamics Llc Radioimaging
US9943274B2 (en) 2004-11-09 2018-04-17 Spectrum Dynamics Medical Limited Radioimaging using low dose isotope
US9316743B2 (en) 2004-11-09 2016-04-19 Biosensors International Group, Ltd. System and method for radioactive emission measurement
EP1709585A4 (en) 2004-01-13 2015-11-25 Biosensors Int Group Ltd Multi-dimensional image reconstruction
US8586932B2 (en) 2004-11-09 2013-11-19 Spectrum Dynamics Llc System and method for radioactive emission measurement
US7734331B2 (en) * 2004-03-02 2010-06-08 General Electric Company Systems, methods and apparatus for preparation, delivery and monitoring of radioisotopes in positron emission tomography
EP1778957A4 (en) 2004-06-01 2015-12-23 Biosensors Int Group Ltd Radioactive-emission-measurement optimization to specific body structures
US20060027756A1 (en) * 2004-08-09 2006-02-09 Ian Thomson Dosimeter having an array of sensors for measuring ionizing radiation, and dosimetry system and method using such a dosimeter
US8571881B2 (en) 2004-11-09 2013-10-29 Spectrum Dynamics, Llc Radiopharmaceutical dispensing, administration, and imaging
WO2007010534A3 (en) 2005-07-19 2009-02-05 Spectrum Dynamics Llc Imaging protocols
US8837793B2 (en) 2005-07-19 2014-09-16 Biosensors International Group, Ltd. Reconstruction stabilizer and active vision
US8615405B2 (en) 2004-11-09 2013-12-24 Biosensors International Group, Ltd. Imaging system customization using data from radiopharmaceutical-associated data carrier
US20060127311A1 (en) * 2004-11-17 2006-06-15 Duke University Radiation dosimetry and blocking antibodies and methods and uses therefor in the treatment of cancer
JP5345383B2 (en) 2005-04-22 2013-11-20 コーニンクレッカ フィリップス エヌ ヴェ Detector pixel, radiation detectors and methods, positron emission tomography system, an imaging detector and method calibrating, invalidation method of detector cells
EP1921982A2 (en) * 2005-08-25 2008-05-21 Philips Electronics N.V. 4d image-based planning methods and apparatus for targeted therapy
US8463552B1 (en) * 2005-10-18 2013-06-11 Kevin J. Black Methods for medicinal dosage determination and diagnosis
WO2007098493A3 (en) * 2006-02-22 2008-04-17 Univ California Large-area flat-panel photon detector with hemispherical pixels and full area coverage
US8112292B2 (en) 2006-04-21 2012-02-07 Medtronic Navigation, Inc. Method and apparatus for optimizing a therapy
US8894974B2 (en) 2006-05-11 2014-11-25 Spectrum Dynamics Llc Radiopharmaceuticals for diagnosis and therapy
US8660635B2 (en) 2006-09-29 2014-02-25 Medtronic, Inc. Method and apparatus for optimizing a computer assisted surgical procedure
US8610075B2 (en) 2006-11-13 2013-12-17 Biosensors International Group Ltd. Radioimaging applications of and novel formulations of teboroxime
JP5457191B2 (en) * 2006-11-14 2014-04-02 コーニンクレッカ フィリップス エヌ ヴェ System for determining the distribution of the radiopharmaceutical in the subject, method and computer program
WO2008075362A3 (en) 2006-12-20 2008-09-12 Shlomo Ben-Haim A method, a system, and an apparatus for using and processing multidimensional data
US7718963B2 (en) * 2007-08-20 2010-05-18 Honeywell International Inc. Passive solid state ionizing radiation sensor
US8521253B2 (en) 2007-10-29 2013-08-27 Spectrum Dynamics Llc Prostate imaging
WO2009082286A1 (en) * 2007-12-21 2009-07-02 St. Jude Medical Ab Implantable analyte rf spectroscopy measuring system
WO2009107040A1 (en) * 2008-02-28 2009-09-03 Philips Intellectual Property & Standards Gmbh Wireless patient monitoring using streaming of medical data with body-coupled communication
US8803075B2 (en) * 2008-04-18 2014-08-12 Saint-Gobain Ceramics & Plastics, Inc. Radiation detector device
US8165658B2 (en) * 2008-09-26 2012-04-24 Medtronic, Inc. Method and apparatus for positioning a guide relative to a base
CN101923173B (en) * 2009-06-10 2014-10-01 圣戈本陶瓷及塑料股份有限公司 And a scintillator detector assembly
US8338788B2 (en) 2009-07-29 2012-12-25 Spectrum Dynamics Llc Method and system of optimized volumetric imaging
US20110218432A1 (en) * 2010-02-05 2011-09-08 Nova R&D, Inc. In Vivo Molecular Imaging
WO2012004757A3 (en) 2010-07-07 2012-06-28 Institut National D'optique Fiber optic radiochromic dosimeter probe and method to make the same
WO2012149552A3 (en) * 2011-04-29 2013-01-10 The Board Of Trustees Of The Leland Stanford Junior University Dual-isotope positron emitting tomography for disease evaluation
WO2012167257A1 (en) 2011-06-03 2012-12-06 Medrad, Inc. System and method for rapid quantitative dynamic molecular imaging scans
US20130046153A1 (en) 2011-08-16 2013-02-21 Elwha LLC, a limited liability company of the State of Delaware Systematic distillation of status data relating to regimen compliance

Citations (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US32361A (en) * 1861-05-21 Portable filter
US423377A (en) * 1890-03-11 Stove for heating soldering-irons
US424453A (en) * 1890-04-01 William f
US3638640A (en) * 1967-11-01 1972-02-01 Robert F Shaw Oximeter and method for in vivo determination of oxygen saturation in blood using three or more different wavelengths
US3972320A (en) * 1974-08-12 1976-08-03 Gabor Ujhelyi Kalman Patient monitoring system
US4163380A (en) * 1977-10-11 1979-08-07 Lockheed Corporation Forming of preconsolidated metal matrix composites
US4326535A (en) * 1980-05-13 1982-04-27 Akron City Hospital Circuit and method for the radiotelemetry of esophageal pH in an ECG radiotelemetry system
US4397313A (en) * 1981-08-03 1983-08-09 Clini-Therm Corporation Multiple microwave applicator system and method for microwave hyperthermia treatment
US4431004A (en) * 1981-10-27 1984-02-14 Bessman Samuel P Implantable glucose sensor
US4494545A (en) * 1980-05-27 1985-01-22 Cordis Corporation Implant telemetry system
US4523279A (en) * 1980-11-24 1985-06-11 Oximetrix, Inc. Apparatus for determining oxygen saturation levels in blood
US4571292A (en) * 1982-08-12 1986-02-18 Case Western Reserve University Apparatus for electrochemical measurements
US4571589A (en) * 1982-11-22 1986-02-18 Cordis Corporation Biomedical implant with high speed, low power two-way telemetry
US4575676A (en) * 1983-04-04 1986-03-11 Advanced Research And Applications Corporation Method and apparatus for radiation testing of electron devices
US4638436A (en) * 1984-09-24 1987-01-20 Labthermics Technologies, Inc. Temperature control and analysis system for hyperthermia treatment
US4651741A (en) * 1985-05-30 1987-03-24 Baxter Travenol Laboratories, Inc. Method and apparatus for determining oxygen saturation in vivo
US4655880A (en) * 1983-08-01 1987-04-07 Case Western Reserve University Apparatus and method for sensing species, substances and substrates using oxidase
US4678916A (en) * 1985-09-18 1987-07-07 Thomson & Nielsen Electronics Ltd. Dosimeter
US4681111A (en) * 1985-04-05 1987-07-21 Siemens-Pacesetter, Inc. Analog and digital telemetry system for an implantable device
US4719919A (en) * 1983-01-21 1988-01-19 Ramm Associates, A Partnership Implantable hyperthermia device and system
US4750495A (en) * 1987-06-05 1988-06-14 Medtronic, Inc. Oxygen sensing pacemaker
US4796641A (en) * 1987-07-06 1989-01-10 Data Sciences, Inc. Device and method for chronic in-vivo measurement of internal body pressure
US4804847A (en) * 1987-01-27 1989-02-14 Medrad, Inc. Radiation detector with an ionizable gas atop an integrated circuit
US4846191A (en) * 1988-05-27 1989-07-11 Data Sciences, Inc. Device for chronic measurement of internal body pressure
US4900422A (en) * 1988-07-05 1990-02-13 Bryan Avron I System for monitoring and reporting the operability and calibration status of a dissolved oxygen sensor
US4919141A (en) * 1987-01-03 1990-04-24 Institute fur Diabetestechnologie Gemeinnutzige Forschungs- und Entwicklungsgesellschaft mbH Implantable electrochemical sensor
US4935345A (en) * 1987-04-07 1990-06-19 Arizona Board Of Regents Implantable microelectronic biochemical sensor incorporating thin film thermopile
US4944299A (en) * 1989-08-08 1990-07-31 Siemens-Pacesetter, Inc. High speed digital telemetry system for implantable device
US4989601A (en) * 1988-05-02 1991-02-05 Medical Engineering & Development Institute, Inc. Method, apparatus, and substance for treating tissue having neoplastic cells
US5008546A (en) * 1990-06-18 1991-04-16 The Regents Of The University Of California Intraoperative beta probe and method of using the same
US5012411A (en) * 1985-07-23 1991-04-30 Charles J. Policastro Apparatus for monitoring, storing and transmitting detected physiological information
US5098547A (en) * 1988-10-11 1992-03-24 Bryan Avron I Dissolved oxygen sensor calibration, monitoring and reporting system
US5109850A (en) * 1990-02-09 1992-05-05 Massachusetts Institute Of Technology Automatic blood monitoring for medication delivery method and apparatus
US5117113A (en) * 1990-07-06 1992-05-26 Thompson And Nielson Electronics Ltd. Direct reading dosimeter
US5117824A (en) * 1990-11-14 1992-06-02 Medtronic, Inc. Apparatus for monitoring electrical physiologic signals
US5126937A (en) * 1986-07-01 1992-06-30 Terumo Kabushiki Kaisha Biological information measurement apparatus
US5127404A (en) * 1990-01-22 1992-07-07 Medtronic, Inc. Telemetry format for implanted medical device
US5137022A (en) * 1990-07-13 1992-08-11 Cook Pacemaker Corporation Synchronous telemetry system and method for an implantable medical device
US5186172A (en) * 1982-03-22 1993-02-16 Mountpelier Investments, S.A. Remote sensing tonometric catheter apparatus
US5193538A (en) * 1989-02-14 1993-03-16 Siemens Aktiengesellschaft In vivo implantable medical device with battery monitoring circuitry
US5197466A (en) * 1983-01-21 1993-03-30 Med Institute Inc. Method and apparatus for volumetric interstitial conductive hyperthermia
US5205294A (en) * 1991-02-19 1993-04-27 Pacific Communications, Inc. Apparatus and methodology for digital telemetry of biomedical signals
US5309085A (en) * 1990-08-21 1994-05-03 Byung Ki Sohn Measuring circuit with a biosensor utilizing ion sensitive field effect transistors
US5324315A (en) * 1993-08-12 1994-06-28 Medtronic, Inc. Closed-loop downlink telemetry and method for implantable medical device
US5330634A (en) * 1992-08-28 1994-07-19 Via Medical Corporation Calibration solutions useful for analyses of biological fluids and methods employing same
US5383909A (en) * 1993-01-29 1995-01-24 Medtronic, Inc. Diagnostic telemetry system for an apparatus for detection and treatment of tachycardia and fibrillation
US5419401A (en) * 1992-07-17 1995-05-30 Avec S.R.L. Oil-pneumatic load control device
US5425361A (en) * 1991-11-28 1995-06-20 Paul-Gerhard Fenzlein Apparatus for the determination of medical, electro-chemical measured values relevant to organic or metabolic functions
US5431171A (en) * 1993-06-25 1995-07-11 The Regents Of The University Of California Monitoring fetal characteristics by radiotelemetric transmission
US5444254A (en) * 1992-06-12 1995-08-22 Thomson And Nielsen Electronics Ltd. Flexible radiation probe
US5480415A (en) * 1993-05-05 1996-01-02 Intermedics, Inc. Apparatus for high speed data communication between an external medical device and an implantable medical device
US5481262A (en) * 1990-08-03 1996-01-02 Bio Medic Data Systems, Inc. System monitoring programmable implanatable transponder
US5497772A (en) * 1993-11-19 1996-03-12 Alfred E. Mann Foundation For Scientific Research Glucose monitoring system
US5507786A (en) * 1994-04-14 1996-04-16 Pacesetter, Inc. System and method for measuring and storing parametric data pertaining to operating characteristics of an implantable medical device
US5517313A (en) * 1995-02-21 1996-05-14 Colvin, Jr.; Arthur E. Fluorescent optical sensor
US5535752A (en) * 1995-02-27 1996-07-16 Medtronic, Inc. Implantable capacitive absolute pressure and temperature monitor system
US5545187A (en) * 1994-02-23 1996-08-13 Pacesetter Ab Medical field detector and telemetry unit for implants
US5549654A (en) * 1994-04-15 1996-08-27 Medtronic, Inc. Interactive interpretation of event markers in body-implantable medical device
US5591217A (en) * 1995-01-04 1997-01-07 Plexus, Inc. Implantable stimulator with replenishable, high value capacitive power source and method therefor
US5593430A (en) * 1995-01-27 1997-01-14 Pacesetter, Inc. Bus system for interconnecting an implantable medical device with a plurality of sensors
US5596199A (en) * 1995-02-06 1997-01-21 Clemson University Passive solid state microdosimeter with electronic readout
US5606163A (en) * 1995-01-11 1997-02-25 The United States Of America As Represented By The Secretary Of The Navy All-optical, rapid readout, fiber-coupled thermoluminescent dosimeter system
US5620472A (en) * 1995-01-12 1997-04-15 Pacesetter, Inc. Apparatus and method for dynamically interpreting and displaying a real-time telemetry link
US5620479A (en) * 1992-11-13 1997-04-15 The Regents Of The University Of California Method and apparatus for thermal therapy of tumors
US5620475A (en) * 1994-04-25 1997-04-15 Siemens Elema Ab Extracorporeally controllable medical implant and method for operating same
US5626630A (en) * 1994-10-13 1997-05-06 Ael Industries, Inc. Medical telemetry system using an implanted passive transponder
US5626862A (en) * 1994-08-02 1997-05-06 Massachusetts Institute Of Technology Controlled local delivery of chemotherapeutic agents for treating solid tumors
US5628324A (en) * 1995-02-04 1997-05-13 Baumann & Haldi S.A. Autonomous system for measuring, processing and transmitting essentially physiological parameters
US5630413A (en) * 1992-07-06 1997-05-20 Sandia Corporation Reliable noninvasive measurement of blood gases
US5656815A (en) * 1996-02-08 1997-08-12 The United States Of America As Represented By The Secretary Of The Navy Thermoluminescence radiation dosimetry using transparent glass containing nanocrystalline phosphor
US5720771A (en) * 1995-08-02 1998-02-24 Pacesetter, Inc. Method and apparatus for monitoring physiological data from an implantable medical device
US5732704A (en) * 1995-10-13 1998-03-31 Neoprobe Corporation Radiation based method locating and differentiating sentinel nodes
US5744805A (en) * 1996-05-07 1998-04-28 University Of Michigan Solid state beta-sensitive surgical probe
US5744804A (en) * 1994-04-05 1998-04-28 Rijksuniversiteit Te Groningen System for determining a compositon of radionuclides
US5752976A (en) * 1995-06-23 1998-05-19 Medtronic, Inc. World wide patient location and data telemetry system for implantable medical devices
US5759199A (en) * 1995-08-02 1998-06-02 Pacesetter, Inc. System and method for ambulatory monitoring and programming of an implantable medical device
US5791344A (en) * 1993-11-19 1998-08-11 Alfred E. Mann Foundation For Scientific Research Patient monitoring system
US5857463A (en) * 1995-10-13 1999-01-12 Neoprobe Corporation Remotely controlled apparatus and system for tracking and locating a source of photoemissions
US5879375A (en) * 1992-08-06 1999-03-09 Electric Boat Corporation Implantable device monitoring arrangement and method
US5891179A (en) * 1997-11-20 1999-04-06 Paceseter, Inc. Method and apparatus for monitoring and displaying lead impedance in real-time for an implantable medical device
US5918110A (en) * 1996-05-31 1999-06-29 Siemens Aktiengesellschaft Method for manufacturing a combination of a pressure sensor and an electrochemical sensor
US5916167A (en) * 1997-10-10 1999-06-29 Neoprobe Corporation Surgical probe apparatus and system
US5928150A (en) * 1997-10-04 1999-07-27 Neoprobe Corporation System for locating and detecting a source of photon emissions
US5932879A (en) * 1996-05-07 1999-08-03 Regents Of The University Of Michigan Solid state beta-sensitive surgical probe
US6015390A (en) * 1998-06-12 2000-01-18 D. Krag Llc System and method for stabilizing and removing tissue
US6047214A (en) * 1998-06-09 2000-04-04 North Carolina State University System and method for powering, controlling, and communicating with multiple inductively-powered devices
US6076009A (en) * 1997-05-05 2000-06-13 The University Of Michigan Solid state beta-sensitive surgical probe
US6087666A (en) * 1998-02-18 2000-07-11 The United States Of America As Represented By The Secretary Of The Navy Optically stimulated luminescent fiber optic radiation dosimeter
US6093381A (en) * 1994-07-13 2000-07-25 Neoprobe Corporation Modulation of the sensitivity of tumor cells to chemotherapeutics
US6172368B1 (en) * 1997-09-12 2001-01-09 Carleton University Method of monitoring radiation using a floating gate field effect transistor dosimeter, and dosimeter for use therein
US6239724B1 (en) * 1997-12-30 2001-05-29 Remon Medical Technologies, Ltd. System and method for telemetrically providing intrabody spatial position
US6240312B1 (en) * 1997-10-23 2001-05-29 Robert R. Alfano Remote-controllable, micro-scale device for use in in vivo medical diagnosis and/or treatment
US6242741B1 (en) * 1998-10-23 2001-06-05 United States Surgical Corporation Radiation detection apparatus
US6259095B1 (en) * 1998-10-23 2001-07-10 Neoprobe Corporation System and apparatus for detecting and locating sources of radiation
US6363940B1 (en) * 1998-05-14 2002-04-02 Calypso Medical Technologies, Inc. System and method for bracketing and removing tissue
US6524786B1 (en) * 1997-08-18 2003-02-25 Amersham Plc Scintillation proximity test

Family Cites Families (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US557702A (en) * 1896-04-07 Water-gage shut-off for boilers
USRE32361E (en) 1979-05-14 1987-02-24 Medtronic, Inc. Implantable telemetry transmission system for analog and digital data
US4361153A (en) 1980-05-27 1982-11-30 Cordis Corporation Implant telemetry system
US4556063A (en) 1980-10-07 1985-12-03 Medtronic, Inc. Telemetry system for a medical device
US4397314A (en) 1981-08-03 1983-08-09 Clini-Therm Corporation Method and apparatus for controlling and optimizing the heating pattern for a hyperthermia system
US4416283A (en) 1981-08-31 1983-11-22 Cordis Corporation Programming and telemetry system for biomedical implantable device
CA1188431A (en) 1981-10-02 1985-06-04 Canadian Astronautics Limited Direct reading dosimeter
GB2140563B (en) 1983-04-27 1987-03-04 Critikon Inc Method and apparatus for zero calibration of oxygen-sensing polarographic devices
US4543953A (en) 1983-07-18 1985-10-01 Cordis Corporation Analog telemetry system for biomedical implant
US4519401A (en) 1983-09-20 1985-05-28 Case Western Reserve University Pressure telemetry implant
FI68734C (en) 1983-11-11 1985-10-10 Seppo Saeynaejaekangas Foerfarande and the arrangement of the Foer telemetrisk maetning hjaertslag Science ECG signal with anvaendande of a magnetically naerfaelt
GB8422876D0 (en) 1984-09-11 1984-10-17 Secr Defence Silicon implant devices
US4703756A (en) 1986-05-06 1987-11-03 The Regents Of The University Of California Complete glucose monitoring system with an implantable, telemetered sensor module
US4976266A (en) 1986-08-29 1990-12-11 United States Department Of Energy Methods of in vivo radiation measurement
US4769547A (en) 1987-01-27 1988-09-06 Medrad, Inc. Personal dosimeter having a volume of gas atop an integrated circuit
US4970391A (en) 1987-01-27 1990-11-13 Medrad, Inc. Radiation detector with an ionizable gas atop an integrated circuit
US4847617A (en) 1987-08-14 1989-07-11 Siemens-Pacesetter, Inc. High speed digital telemetry system for implantable devices
GB8726933D0 (en) 1987-11-18 1987-12-23 Cadell T E Telemetry system
US5354314A (en) 1988-12-23 1994-10-11 Medical Instrumentation And Diagnostics Corporation Three-dimensional beam localization apparatus and microscope for stereotactic diagnoses or surgery mounted on robotic type arm
US5264843A (en) 1989-04-05 1993-11-23 Siemens Pacesetter, Inc. High speed reflected impedance telemetry system for implantable medical device
US5166073A (en) 1989-05-05 1992-11-24 The Dow Chemical Company Miniaturized sensor for ionizing radiation
US5354319A (en) 1990-01-22 1994-10-11 Medtronic, Inc. Telemetry system for an implantable medical device
US5163380A (en) 1990-08-09 1992-11-17 United States Of America Method and apparatus for assessing metabolic behavioral and physiological status of animals
JP2646848B2 (en) 1990-11-30 1997-08-27 日本電気株式会社 Method of measuring the glucose sensor
US5159262A (en) 1991-07-09 1992-10-27 Cascade Microtech, Inc. Method for measuring the electrical and optical performance of on-wafer microwave devices
NL9200207A (en) 1992-02-05 1993-09-01 Nedap Nv Implantable biomedical sensor device, in particular for measurement of the glucose concentration.
ES2170090T3 (en) 1992-11-09 2002-08-01 Ilife Systems Inc Apparatus and method for remote monitoring of physiological parameters.
DE4444577B4 (en) 1993-12-15 2005-02-10 Bridgestone Corp. A process for producing an optical waveguide
US5476488A (en) 1993-12-15 1995-12-19 Pacesetter, Inc. Telemetry system power control for implantable medical devices
US5470345A (en) 1994-06-16 1995-11-28 Medtronic, Inc. Implantable medical device with multi-layered ceramic enclosure
US5466246A (en) 1994-07-29 1995-11-14 Pacesetter, Inc. Telemetry receiver for implantable device, incorporating digital signal processing
US5571148A (en) 1994-08-10 1996-11-05 Loeb; Gerald E. Implantable multichannel stimulator
US5562713A (en) 1995-01-18 1996-10-08 Pacesetter, Inc. Bidirectional telemetry apparatus and method for implantable device
US5556421A (en) 1995-02-22 1996-09-17 Intermedics, Inc. Implantable medical device with enclosed physiological parameter sensors or telemetry link
US5564434A (en) 1995-02-27 1996-10-15 Medtronic, Inc. Implantable capacitive absolute pressure and temperature sensor
US5840148A (en) * 1995-06-30 1998-11-24 Bio Medic Data Systems, Inc. Method of assembly of implantable transponder
US5811814A (en) * 1996-02-12 1998-09-22 Cordis Corporation Radiation measuring catheter apparatus and method
US5682888A (en) * 1996-06-13 1997-11-04 Neoprobe Corporation Apparatus and system for detecting and locating photon emissions with remote switch control
US5987350A (en) * 1997-10-10 1999-11-16 Neoprobe Corporation Surgical probe apparatus and system
CA2318471A1 (en) * 1998-01-06 1999-07-15 Alexander V. Kirichenko Nuclear scintigraphic assessment of mucosal function
US6295680B1 (en) * 1998-07-05 2001-10-02 The Regents Of The University Of Michigan Method for detecting early atherosclerosis and vascular damage using radioactive tracers and intravascular radiation detection devices
DE69939592D1 (en) * 1998-09-30 2008-10-30 Sicel Technologies Inc Methods, systems, and associated implantable devices for dynamic monitoring of tumors
US6272373B1 (en) * 1998-10-23 2001-08-07 Neoprobe Corporation Scanning system and method for locating sources of radiation emission
US6444475B1 (en) * 1999-08-02 2002-09-03 Alltech Associates, Inc. Ion chromatography apparatus and method for removing gas prior to sample detection
EP1474038A1 (en) * 2002-01-29 2004-11-10 Sicel Technologies, Inc. Implantable sensor housing and fabrication methods

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US32361A (en) * 1861-05-21 Portable filter
US423377A (en) * 1890-03-11 Stove for heating soldering-irons
US424453A (en) * 1890-04-01 William f
US3638640A (en) * 1967-11-01 1972-02-01 Robert F Shaw Oximeter and method for in vivo determination of oxygen saturation in blood using three or more different wavelengths
US3972320A (en) * 1974-08-12 1976-08-03 Gabor Ujhelyi Kalman Patient monitoring system
US4163380A (en) * 1977-10-11 1979-08-07 Lockheed Corporation Forming of preconsolidated metal matrix composites
US4326535A (en) * 1980-05-13 1982-04-27 Akron City Hospital Circuit and method for the radiotelemetry of esophageal pH in an ECG radiotelemetry system
US4494545A (en) * 1980-05-27 1985-01-22 Cordis Corporation Implant telemetry system
US4523279A (en) * 1980-11-24 1985-06-11 Oximetrix, Inc. Apparatus for determining oxygen saturation levels in blood
US4397313A (en) * 1981-08-03 1983-08-09 Clini-Therm Corporation Multiple microwave applicator system and method for microwave hyperthermia treatment
US4431004A (en) * 1981-10-27 1984-02-14 Bessman Samuel P Implantable glucose sensor
US5186172A (en) * 1982-03-22 1993-02-16 Mountpelier Investments, S.A. Remote sensing tonometric catheter apparatus
US4571292A (en) * 1982-08-12 1986-02-18 Case Western Reserve University Apparatus for electrochemical measurements
US4571589A (en) * 1982-11-22 1986-02-18 Cordis Corporation Biomedical implant with high speed, low power two-way telemetry
US4719919A (en) * 1983-01-21 1988-01-19 Ramm Associates, A Partnership Implantable hyperthermia device and system
US5197466A (en) * 1983-01-21 1993-03-30 Med Institute Inc. Method and apparatus for volumetric interstitial conductive hyperthermia
US4575676A (en) * 1983-04-04 1986-03-11 Advanced Research And Applications Corporation Method and apparatus for radiation testing of electron devices
US4655880A (en) * 1983-08-01 1987-04-07 Case Western Reserve University Apparatus and method for sensing species, substances and substrates using oxidase
US4638436A (en) * 1984-09-24 1987-01-20 Labthermics Technologies, Inc. Temperature control and analysis system for hyperthermia treatment
US4681111A (en) * 1985-04-05 1987-07-21 Siemens-Pacesetter, Inc. Analog and digital telemetry system for an implantable device
US4651741A (en) * 1985-05-30 1987-03-24 Baxter Travenol Laboratories, Inc. Method and apparatus for determining oxygen saturation in vivo
US5012411A (en) * 1985-07-23 1991-04-30 Charles J. Policastro Apparatus for monitoring, storing and transmitting detected physiological information
US4678916A (en) * 1985-09-18 1987-07-07 Thomson & Nielsen Electronics Ltd. Dosimeter
US5126937A (en) * 1986-07-01 1992-06-30 Terumo Kabushiki Kaisha Biological information measurement apparatus
US4919141A (en) * 1987-01-03 1990-04-24 Institute fur Diabetestechnologie Gemeinnutzige Forschungs- und Entwicklungsgesellschaft mbH Implantable electrochemical sensor
US4804847A (en) * 1987-01-27 1989-02-14 Medrad, Inc. Radiation detector with an ionizable gas atop an integrated circuit
US4935345A (en) * 1987-04-07 1990-06-19 Arizona Board Of Regents Implantable microelectronic biochemical sensor incorporating thin film thermopile
US4750495A (en) * 1987-06-05 1988-06-14 Medtronic, Inc. Oxygen sensing pacemaker
US4796641A (en) * 1987-07-06 1989-01-10 Data Sciences, Inc. Device and method for chronic in-vivo measurement of internal body pressure
US4989601A (en) * 1988-05-02 1991-02-05 Medical Engineering & Development Institute, Inc. Method, apparatus, and substance for treating tissue having neoplastic cells
US4846191A (en) * 1988-05-27 1989-07-11 Data Sciences, Inc. Device for chronic measurement of internal body pressure
US4900422A (en) * 1988-07-05 1990-02-13 Bryan Avron I System for monitoring and reporting the operability and calibration status of a dissolved oxygen sensor
US5098547A (en) * 1988-10-11 1992-03-24 Bryan Avron I Dissolved oxygen sensor calibration, monitoring and reporting system
US5193538A (en) * 1989-02-14 1993-03-16 Siemens Aktiengesellschaft In vivo implantable medical device with battery monitoring circuitry
US4944299A (en) * 1989-08-08 1990-07-31 Siemens-Pacesetter, Inc. High speed digital telemetry system for implantable device
US5127404A (en) * 1990-01-22 1992-07-07 Medtronic, Inc. Telemetry format for implanted medical device
US5314450A (en) * 1990-01-22 1994-05-24 Medtronic, Inc. Dual channel telemetry for implanted medical device
US5109850A (en) * 1990-02-09 1992-05-05 Massachusetts Institute Of Technology Automatic blood monitoring for medication delivery method and apparatus
US5008546A (en) * 1990-06-18 1991-04-16 The Regents Of The University Of California Intraoperative beta probe and method of using the same
US5117113A (en) * 1990-07-06 1992-05-26 Thompson And Nielson Electronics Ltd. Direct reading dosimeter
US5137022A (en) * 1990-07-13 1992-08-11 Cook Pacemaker Corporation Synchronous telemetry system and method for an implantable medical device
US5481262A (en) * 1990-08-03 1996-01-02 Bio Medic Data Systems, Inc. System monitoring programmable implanatable transponder
US5309085A (en) * 1990-08-21 1994-05-03 Byung Ki Sohn Measuring circuit with a biosensor utilizing ion sensitive field effect transistors
US5117824A (en) * 1990-11-14 1992-06-02 Medtronic, Inc. Apparatus for monitoring electrical physiologic signals
US5205294A (en) * 1991-02-19 1993-04-27 Pacific Communications, Inc. Apparatus and methodology for digital telemetry of biomedical signals
US5425361A (en) * 1991-11-28 1995-06-20 Paul-Gerhard Fenzlein Apparatus for the determination of medical, electro-chemical measured values relevant to organic or metabolic functions
US5444254A (en) * 1992-06-12 1995-08-22 Thomson And Nielsen Electronics Ltd. Flexible radiation probe
US5630413A (en) * 1992-07-06 1997-05-20 Sandia Corporation Reliable noninvasive measurement of blood gases
US5419401A (en) * 1992-07-17 1995-05-30 Avec S.R.L. Oil-pneumatic load control device
US5879375A (en) * 1992-08-06 1999-03-09 Electric Boat Corporation Implantable device monitoring arrangement and method
US5505828A (en) * 1992-08-28 1996-04-09 Via Medical Corporation Calibration solutions useful for analysis of biological fluids and methods employing same
US5330634A (en) * 1992-08-28 1994-07-19 Via Medical Corporation Calibration solutions useful for analyses of biological fluids and methods employing same
US5620479A (en) * 1992-11-13 1997-04-15 The Regents Of The University Of California Method and apparatus for thermal therapy of tumors
US5383909A (en) * 1993-01-29 1995-01-24 Medtronic, Inc. Diagnostic telemetry system for an apparatus for detection and treatment of tachycardia and fibrillation
US5480415A (en) * 1993-05-05 1996-01-02 Intermedics, Inc. Apparatus for high speed data communication between an external medical device and an implantable medical device
US5538005A (en) * 1993-06-25 1996-07-23 The Regents Of The University Of California B'method for monitoring fetal characteristics by radiotelemetric transmission
US5431171A (en) * 1993-06-25 1995-07-11 The Regents Of The University Of California Monitoring fetal characteristics by radiotelemetric transmission
US5324315A (en) * 1993-08-12 1994-06-28 Medtronic, Inc. Closed-loop downlink telemetry and method for implantable medical device
US5497772A (en) * 1993-11-19 1996-03-12 Alfred E. Mann Foundation For Scientific Research Glucose monitoring system
US5791344A (en) * 1993-11-19 1998-08-11 Alfred E. Mann Foundation For Scientific Research Patient monitoring system
US5545187A (en) * 1994-02-23 1996-08-13 Pacesetter Ab Medical field detector and telemetry unit for implants
US5744804A (en) * 1994-04-05 1998-04-28 Rijksuniversiteit Te Groningen System for determining a compositon of radionuclides
US5507786A (en) * 1994-04-14 1996-04-16 Pacesetter, Inc. System and method for measuring and storing parametric data pertaining to operating characteristics of an implantable medical device
US5549654A (en) * 1994-04-15 1996-08-27 Medtronic, Inc. Interactive interpretation of event markers in body-implantable medical device
US5620475A (en) * 1994-04-25 1997-04-15 Siemens Elema Ab Extracorporeally controllable medical implant and method for operating same
US6093381A (en) * 1994-07-13 2000-07-25 Neoprobe Corporation Modulation of the sensitivity of tumor cells to chemotherapeutics
US5626862A (en) * 1994-08-02 1997-05-06 Massachusetts Institute Of Technology Controlled local delivery of chemotherapeutic agents for treating solid tumors
US5626630A (en) * 1994-10-13 1997-05-06 Ael Industries, Inc. Medical telemetry system using an implanted passive transponder
US5591217A (en) * 1995-01-04 1997-01-07 Plexus, Inc. Implantable stimulator with replenishable, high value capacitive power source and method therefor
US5606163A (en) * 1995-01-11 1997-02-25 The United States Of America As Represented By The Secretary Of The Navy All-optical, rapid readout, fiber-coupled thermoluminescent dosimeter system
US5620472A (en) * 1995-01-12 1997-04-15 Pacesetter, Inc. Apparatus and method for dynamically interpreting and displaying a real-time telemetry link
US5593430A (en) * 1995-01-27 1997-01-14 Pacesetter, Inc. Bus system for interconnecting an implantable medical device with a plurality of sensors
US5628324A (en) * 1995-02-04 1997-05-13 Baumann & Haldi S.A. Autonomous system for measuring, processing and transmitting essentially physiological parameters
US5596199A (en) * 1995-02-06 1997-01-21 Clemson University Passive solid state microdosimeter with electronic readout
US5517313A (en) * 1995-02-21 1996-05-14 Colvin, Jr.; Arthur E. Fluorescent optical sensor
US5535752A (en) * 1995-02-27 1996-07-16 Medtronic, Inc. Implantable capacitive absolute pressure and temperature monitor system
US5752976A (en) * 1995-06-23 1998-05-19 Medtronic, Inc. World wide patient location and data telemetry system for implantable medical devices
US5720771A (en) * 1995-08-02 1998-02-24 Pacesetter, Inc. Method and apparatus for monitoring physiological data from an implantable medical device
US5759199A (en) * 1995-08-02 1998-06-02 Pacesetter, Inc. System and method for ambulatory monitoring and programming of an implantable medical device
US5732704A (en) * 1995-10-13 1998-03-31 Neoprobe Corporation Radiation based method locating and differentiating sentinel nodes
US5857463A (en) * 1995-10-13 1999-01-12 Neoprobe Corporation Remotely controlled apparatus and system for tracking and locating a source of photoemissions
US5656815A (en) * 1996-02-08 1997-08-12 The United States Of America As Represented By The Secretary Of The Navy Thermoluminescence radiation dosimetry using transparent glass containing nanocrystalline phosphor
US5932879A (en) * 1996-05-07 1999-08-03 Regents Of The University Of Michigan Solid state beta-sensitive surgical probe
US5744805A (en) * 1996-05-07 1998-04-28 University Of Michigan Solid state beta-sensitive surgical probe
US5918110A (en) * 1996-05-31 1999-06-29 Siemens Aktiengesellschaft Method for manufacturing a combination of a pressure sensor and an electrochemical sensor
US6076009A (en) * 1997-05-05 2000-06-13 The University Of Michigan Solid state beta-sensitive surgical probe
US6524786B1 (en) * 1997-08-18 2003-02-25 Amersham Plc Scintillation proximity test
US6172368B1 (en) * 1997-09-12 2001-01-09 Carleton University Method of monitoring radiation using a floating gate field effect transistor dosimeter, and dosimeter for use therein
US5928150A (en) * 1997-10-04 1999-07-27 Neoprobe Corporation System for locating and detecting a source of photon emissions
US5916167A (en) * 1997-10-10 1999-06-29 Neoprobe Corporation Surgical probe apparatus and system
US6240312B1 (en) * 1997-10-23 2001-05-29 Robert R. Alfano Remote-controllable, micro-scale device for use in in vivo medical diagnosis and/or treatment
US5891179A (en) * 1997-11-20 1999-04-06 Paceseter, Inc. Method and apparatus for monitoring and displaying lead impedance in real-time for an implantable medical device
US6239724B1 (en) * 1997-12-30 2001-05-29 Remon Medical Technologies, Ltd. System and method for telemetrically providing intrabody spatial position
US6087666A (en) * 1998-02-18 2000-07-11 The United States Of America As Represented By The Secretary Of The Navy Optically stimulated luminescent fiber optic radiation dosimeter
US6363940B1 (en) * 1998-05-14 2002-04-02 Calypso Medical Technologies, Inc. System and method for bracketing and removing tissue
US6047214A (en) * 1998-06-09 2000-04-04 North Carolina State University System and method for powering, controlling, and communicating with multiple inductively-powered devices
US6015390A (en) * 1998-06-12 2000-01-18 D. Krag Llc System and method for stabilizing and removing tissue
US6242741B1 (en) * 1998-10-23 2001-06-05 United States Surgical Corporation Radiation detection apparatus
US6259095B1 (en) * 1998-10-23 2001-07-10 Neoprobe Corporation System and apparatus for detecting and locating sources of radiation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090018403A1 (en) * 2007-07-12 2009-01-15 Sicel Technologies, Inc. Trackable implantable sensor devices, systems, and related methods of operation
US9439585B2 (en) 2008-02-04 2016-09-13 Ascensia Diabetes Care Holdings Ag Semiconductor based analyte sensors and methods
US20100298679A1 (en) * 2008-02-04 2010-11-25 Bayer Healthcare Llc Semiconductor based analyte sensors and methods
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US20110172559A1 (en) * 2008-09-19 2011-07-14 Bayer Healthcare Llc Lancet Analyte Sensors and Methods of Manufacturing
US20110180405A1 (en) * 2008-09-19 2011-07-28 Bayer Healthcare Llc Analyte Sensors, Systems, Testing Apparatus and Manufacturing Methods
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US20110171071A1 (en) * 2008-09-19 2011-07-14 Bayer Healthcare Llc Analyte Sensors, Testing Apparatus and Manufacturing Methods
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US10022080B2 (en) 2008-09-19 2018-07-17 Ascensia Diabetes Care Holdings Ag Analyte sensors, systems, testing apparatus and manufacturing methods
US20120241628A1 (en) * 2009-05-12 2012-09-27 Juergen Hesser Detector for the detection of ionizing radiation
US20110201993A1 (en) * 2009-08-19 2011-08-18 Olympus Medical Systems Corp. Detecting apparatus and medical control method
WO2014143222A1 (en) * 2012-05-30 2014-09-18 Lucerno Dynamics, Llc System for the detection of gamma radiation from a radioactive analyte
US9002438B2 (en) 2012-05-30 2015-04-07 Lucerno Dynamics System for the detection of gamma radiation from a radioactive analyte
US9939533B2 (en) 2012-05-30 2018-04-10 Lucerno Dynamics, Llc System and method for the detection of gamma radiation from a radioactive analyte
WO2015121843A1 (en) * 2014-02-17 2015-08-20 Winmedical S.R.L. A device for measuring a plurality of parameters in patient subject to a treatment with radiopharmaceuticals
WO2017087945A1 (en) * 2015-11-20 2017-05-26 Acea Biosciences, Inc. Cell-substrate impedance monitoring of cancer cells

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