pyrophosphate and Necrosis

Vascular targeting agents (VTAs) for the treatment of cancer are designed to cause a rapid and selective shutdown of the blood vessels of tumors. Unlike antiangiogenic drugs that inhibit the formation of new vessels, VTAs occlude the pre-existing blood vessels of tumors to cause tumor cell death from ischemia and extensive hemorrhagic necrosis. Tumor selectivity is conferred by differences in the pathophysiology of tumor versus normal tissue vessels (e.g., increased proliferation and fragility, and up-regulated proteins). VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance. VTAs are expected to show the greatest therapeutic benefit as part of combined modality regimens. Preclinical studies have shown VTA-induced enhancement of the effects of conventional chemotherapeutic agents, radiation, hyperthermia, radioimmunotherapy, and antiangiogenic agents. There are broadly two types of VTAs, small molecules and ligand-based, which are grouped together, because they both cause acute vascular shutdown in tumors leading to massive necrosis. The small molecules include the microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and Oxi 4503, and the flavonoid, DMXAA. Ligand-based VTAs use antibodies, peptides, or growth factors that bind selectively to tumor versus normal vessels to target tumors with agents that occlude blood vessels. The ligand-based VTAs include fusion proteins (e.g., vascular endothelial growth factor linked to the plant toxin gelonin), immunotoxins (e.g., monoclonal antibodies to endoglin conjugated to ricin A), antibodies linked to cytokines, liposomally encapsulated drugs, and gene therapy approaches. Combretastatin A-4 disodium phosphate, ZD6126, AVE8062, and DMXAA are undergoing clinical evaluation. Phase I monotherapy studies have shown that the agents are tolerated with some demonstration of single agent efficacy. Because efficacy is expected when the agents are used with conventional chemotherapeutic drugs or radiation, the results of Phase II combination studies are eagerly awaited.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Cell Division; Clinical Trials as Topic; Diphosphates; Genetic Therapy; Humans; Hypoxia; Immunotoxins; Ligands; Models, Biological; Necrosis; Neoplasms; Organophosphorus Compounds; Peptides; Radioimmunotherapy; Stilbenes; Time Factors; Up-Regulation; Xanthones

Topics: Animals; Diphosphates; Heart; Humans; Myocardial Ischemia; Myocardium; Necrosis; Radionuclide Imaging; Reperfusion Injury; Technetium Tc 99m Pyrophosphate

The major value of hot-spot imaging of the myocardium is its ability to define areas of necrosis rather than areas of diminished blood flow or cellular function. Applications of hot-spot imaging include the diagnosis and quantitation of myocardial infarction, myocarditis, and cardiac transplant rejection. The two agents in clinical use, 99mTc-Pyrophosphate and radiolabeled antimyosin, are discussed.

Topics: Animals; Antibodies; Coronary Disease; Diphosphates; Graft Rejection; Heart Transplantation; Humans; Myocardial Infarction; Myocarditis; Myocardium; Myosins; Necrosis; Postoperative Complications; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

The necropsy findings of a large cell lymphoma involving only the pericardium and myocardium in a 62-year-old woman are reported. The initial presenting symptoms were heart failure followed by rapidly progressive heart block. The diagnosis of cardiac lymphoma was suggested by gallium and blood pool isotope studies, and was subsequently confirmed by operative myocardial biopsy. The clinical course was abrupt, and the patient died before therapy was instituted. While primary cardiac lymphoma is an extremely rare condition, experience in this case suggests that noninvasive isotope studies, particularly gallium and blood pool, are helpful in the diagnosis of atypical cardiomyopathy.

Topics: Diphosphates; Female; Gallium Radioisotopes; Heart Neoplasms; Humans; Lymphoma; Middle Aged; Myocardium; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Contusions; Coronary Artery Bypass; Coronary Disease; Diagnosis, Differential; Diphosphates; Heart Injuries; Humans; Myocardial Infarction; Myocardium; Necrosis; Radionuclide Imaging; Technetium; Time Factors

An effective, nontoxic, tumor-specific immunotherapy is the ultimate goal in the battle against cancer, especially the metastatic disease. Checkpoint blockade-based immunotherapies have been shown to be extraordinarily effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. Here, we show that Zn-pyrophosphate (ZnP) nanoparticles loaded with the photosensitizer pyrolipid (ZnP@pyro) can kill tumor cells upon irradiation with light directly by inducing apoptosis and/or necrosis and indirectly by disrupting tumor vasculature and increasing tumor immunogenicity. Furthermore, immunogenic ZnP@pyro photodynamic therapy (PDT) treatment sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only eradicating the primary 4T1 breast tumor but also significantly preventing metastasis to the lung. The abscopal effects on both 4T1 and TUBO bilateral syngeneic mouse models further demonstrate that ZnP@pyro PDT treatment combined with anti-PD-L1 results in the eradication of light-irradiated primary tumors and the complete inhibition of untreated distant tumors by generating a systemic tumor-specific cytotoxic T cell response. These findings indicate that nanoparticle-mediated PDT can potentiate the systemic efficacy of checkpoint blockade immunotherapies by activating the innate and adaptive immune systems in tumor microenvironment.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Chlorophyll; Combined Modality Therapy; Diphosphates; Humans; Immunotherapy; Light; Lipids; Lung Neoplasms; Mice; Nanoparticles; Necrosis; Neoplasm Metastasis; Photochemotherapy; Photosensitizing Agents; Zinc

Extracellular ATP is an important signaling molecule mediating quite divergent specific biological effects. Even though recent studies suggest a potential role of ATP in cancer progress, its real impact in chemotherapeutic efficacy remains unclear. In the present study, we investigated the effect of ATP on the cytotoxicity of doxorubicin in various cancer cell types and found that ATP had no effect on doxorubicin cytotoxicity in colon, prostate, breast, and cervical cancers or in osteosarcoma. In contrast, ATP has divergent effects on lung cancer cells: it can protect against doxorubicin-induced cell death in non-metastatic lung cancer CL1.0 cells, but not in highly metastatic CL1.5 cells. Both apoptotic (characterized by sub-G(1) peak, caspase 3 activation, poly(ADP-ribose) polymerase-1 cleavage) and necrotic (characterized by propidium iodide uptake and ROS production) features induced by doxorubicin in CL1.0 cells were reduced by ATP. In addition, ATP attenuated p53 accumulation, DNA damage (assessed by poly(ADP-ribose) formation and the comet assay) and topoisomerase II inhibition after doxorubicin treatment, and doxorubicin cytotoxicity was diminished by the p53 inhibitor pifithrin-α. Moreover, UTP, UDP, ADP, and pyrophosphate sodium pyrophosphate tetrabasic decahydrate diminished the antitumor effect of doxorubicin in CL1.0 cells, whereas purinergic P2 receptors antagonists did not abrogate the action of ATP. In summary, ATP fails to alter the antitumor efficacy of doxorubicin in most cancer cell types, except in CL1.0 cells, in which pyrophosphate mediates the cell protection afforded by ATP via attenuation of reactive oxygen species production, DNA damage, p53 accumulation, and caspase activation.

Topics: Adenosine Triphosphate; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Comet Assay; Diphosphates; Doxorubicin; Humans; Necrosis; Real-Time Polymerase Chain Reaction

Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and >95% tumor necrosis 24h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Cell Survival; Cells, Cultured; Diphosphates; Endothelial Cells; Female; Free Radicals; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C3H; Microtubules; Necrosis; Neovascularization, Physiologic; Regional Blood Flow; Sarcoma, Experimental; Stilbenes; Tubulin Modulators; Tumor Stem Cell Assay

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24h and extensive haemorrhagic necrosis by 48h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p<0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bibenzyls; Bone Neoplasms; Cell Proliferation; Diphosphates; Disease Models, Animal; Doxorubicin; Drug Evaluation, Preclinical; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma, Ewing; Stilbenes

Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway-targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Marrow Cells; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cyclophosphamide; Diphosphates; Dose-Response Relationship, Drug; Endothelial Cells; Green Fluorescent Proteins; Humans; Mice; Microvessels; Necrosis; Neovascularization, Pathologic; Stem Cells; Stilbenes; Xenograft Model Antitumor Assays

Oxi4503 is a potent vascular targeting agent belonging to the family of combretastatins. These agents produce an acute reduction in tumor blood flow leading to tumor necrosis. Despite evidence of its efficacy in certain malignancies, the effect on colorectal liver metastases remains largely unknown. This study investigates the effect of Oxi4503 on colorectal liver metastases in a murine model.. The effect of a single dose of Oxi4503 on established tumors in a murine model of colorectal liver metastases was assessed following administration of 1-50 mg/kg Oxi4503. In addition, the effects of continuous, daily and intermittent dosing (1-5 mg/kg) on tumor necrosis and growth were studied by quantitative histological and stereological analysis. The effect of multiple dosing on long-term survival was also assessed using the Kaplan-Meier analysis. The microvascular effects of therapy were studied by scanning electron microscopy of microvascular resin casts.. A single dose of 5 or 50 mg/kg of Oxi4503 produced significant tumor necrosis compared to the controls. Subcutaneous continuous dosing infusion with Oxi4503 at 1 mg/kg/day reduced tumor growth compared to the controls, but was associated with marked systemic toxicity. Daily administration over 21 days was associated with significant mortality. Intermittent dosing of Oxi4503 (two doses, 3 days apart) produced the greatest reduction in tumor growth with minimal toxicity and conferred a significant survival advantage. Microvascular casts demonstrated significant disruption of tumor vessels.. A single dose of Oxi4503 produced significant necrosis and microvascular injury in colorectal liver metastases. Intermittent dosing with Oxi4503 produced the maximum reduction in tumor growth, minimal toxicity, and a significant improvement in survival. Oxi4503 is a potential anticancer agent. Further research into its mechanism of action and its synergistic use with other therapies is warranted.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Diphosphates; Dose-Response Relationship, Drug; Drug Administration Schedule; Infusion Pumps, Implantable; Infusions, Parenteral; Injections, Intraperitoneal; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred CBA; Microcirculation; Necrosis; Regional Blood Flow; Stilbenes; Time Factors

The contribution of bone marrow-derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cell Hypoxia; Cell Line, Tumor; Diphosphates; Endothelial Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Necrosis; Neoplasm Transplantation; Neoplasms, Experimental; Neovascularization, Pathologic; Stem Cells; Stilbenes

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

Topics: Animals; Apoptosis; Diphosphates; Endothelial Cells; Female; Fluorescence; Hemangioendothelioma; Immunohistochemistry; Male; Mice; Mice, SCID; Necrosis; Permeability; Regional Blood Flow; Stilbenes; Vascular Endothelial Growth Factor A

Previous recommendations regarding the "safe" period of tourniquet hemostasis were based largely on studies of ischemia distal to the tourniquet. This study quantitatively analyzed skeletal muscle injury induced beneath and distal to a pneumatic tourniquet applied to the hindlimbs of rabbits for 1, 2, or 4 hours with a cuff inflation pressure of 125, 200, or 350 mm Hg. Technetium Tc 99m pyrophosphate incorporation after systemic injection (Tc 99 uptake) and correlative histology were used to evaluate tissue damage 2 days after tourniquet application. Compared with the contralateral control limbs, compression and ischemia induced statistically significant increases in Tc 99 uptake in the thigh and leg regions of all groups. Pyrophosphate incorporation was significantly greater in the thigh region than in the leg region after 2 hours of compression in the 200 and 350 mm Hg pressure groups and following 4 hours of compression in all pressure groups. Focal and regional fiber necrosis and degeneration were observed in thigh muscles after 2 hours of tourniquet compression. Two hours of continuous tourniquet application at clinically relevant cuff inflation pressures induced significant skeletal muscle necrosis beneath the tourniquet. Use of the lowest possible inflation pressure for a limited duration should minimize the degree of tissue injury caused by tourniquet application.

Topics: Animals; Diphosphates; Hemostasis, Surgical; Hindlimb; Muscles; Necrosis; Pressure; Rabbits; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Tourniquets

Patients with acute arterial occlusion may suffer from significant muscle necrosis. It is important to determine the amount of regional muscle necrosis for prognostic purposes and evaluation of therapy. We have used technetium-99m-pyrophosphate (PPi) with single photon emission computed tomography (SPECT) to quantitate muscle necrosis. A canine gracilis muscle ischaemia model was used. PPi was injected 1.5 h before the muscle preparation was removed from the dog. SPECT was performed on the muscle preparations. An automatic edge detection program using the threshold technique determined the number of pixels with significant PPi activity in each transaxial section. Volume was calculated by summing the number of pixels with significant PPi activity and multiplying by the voxel size. The results were compared with quantitation using computerized planimetry with nitroblue tetrazolium staining (correlation coefficient = 0.93). PPi with SPECT is an accurate method for quantiating muscle necrosis.

Topics: Animals; Diphosphates; Dogs; Muscles; Necrosis; Technetium; Technetium Tc 99m Pyrophosphate; Tomography, Emission-Computed, Single-Photon

The possibility of myocardial necrosis occurrence in coronary failure proceeding as atypical myocardial infarction was examined in 176 patients with chronic types of coronary heart disease and in experiments with 16 dogs with reversible coronary failure simulated in chronic tests. 99mTe-labeled pyrophosphate myocardial scintigraphy was used in the clinical studies. Myocardial pyrophosphate accumulation was recorded in 37% of patients with angina pectoris without a history of myocardial infarction and 73% myocardial infarction survivals. Histological evidence for small myocardial necroses at various stages of their development was found in 12 dogs. Recurrent transient myocardial ischemias were shown to be able to lead to myocardial necroses that are not always followed by a typical course of acute myocardial infarction.

Topics: Angina Pectoris; Animals; Chronic Disease; Coronary Disease; Diphosphates; Dogs; Heart; Myocardium; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Ischemia-reperfusion damage to skeletal muscle may cause serious local as well as systemic complications, its impact predominantly related to the quantity of ischemic muscle in the lower extremity. To date, there has been no noninvasive method of estimating that quantity. The authors used single photon emission computed tomography (SPECT) to quantify the volume of muscle that takes up technetium-99 pyrophosphate above a baseline threshold. Compared with the standard technique of staining slices of the muscle with nitroblue tetrazolium they found a close correlation using SPECT (r = 0.88, p less than 0.01, n = 19) in the canine model. In humans, this clinically applicable noninvasive technique may allow the surgeon to document accurately the extent of muscle necrosis in the lower extremity, to anticipate the impact of an ischemia-reperfusion injury and evaluate methods of reducing the extent of post-ischemic skeletal muscle necrosis.

Topics: Animals; Diphosphates; Dogs; Leg; Muscles; Necrosis; Nitroblue Tetrazolium; Reperfusion Injury; Technetium; Technetium Tc 99m Pyrophosphate; Tomography, Emission-Computed

Skeletal muscle necrosis will result from prolonged periods of ischemia. The purpose of this study was to develop a method to estimate the extent of necrosis using nitroblue tetrazolium staining and technetium scanning. The bilateral canine gracilis muscle preparation with total vascular isolation was exposed to 4 hr of complete normothermic ischemia followed by reperfusion. After 45 hr of reperfusion 99mTc pyrophosphate (PYP) was injected and 3 hr later the muscles were harvested, cut into six slices, and stained with nitroblue tetrazolium. Biopsies were taken from tetrazolium-positive and -negative areas for electron microscopy to confirm the ability of the stain to distinguish viable from necrotic muscle. Computerized planimetry of the staining pattern was used to estimate the extent of necrosis as a percentage of the total muscle. Electron microscopy confirmed the validity of nitroblue tetrazolium to discriminate between viable and necrotic skeletal muscle in this experimental model. After 4 hr of ischemia the percentage necrosis was 30.2 +/- 6.1% (mean +/- SEM, n = 12), there was no difference in the extent of necrosis in left vs right paired muscles, using tetrazolium staining or technetium PYP uptake. There was a statistically significant correlation between the percentage necrosis and the density of 99mTc PYP uptake per muscle (r = 0.83, P less than 0.001) and per slice (r = 0.94, P less than 0.001). This study demonstrates the ability of tetrazolium staining to accurately differentiate between viable and necrotic skeletal muscle and provides a reproducible method for estimating the extent of necrosis in the gracilis muscle model.

Topics: Animals; Diphosphates; Dogs; In Vitro Techniques; Ischemia; Muscles; Necrosis; Nitroblue Tetrazolium; Radionuclide Imaging; Staining and Labeling; Technetium; Technetium Tc 99m Pyrophosphate

A retrospective review was done of 34 extremities studied between 1981 and 1985 with technetium-99m pyrophosphate scanning; 22 were subsequently amputated. Results of detailed pathologic examination or immediate postoperative examination of the resected extremity were available in 16 cases. In these cases, scanning had allowed correct prediction of the level of amputation and of the specific areas of muscle infarction in 13 cases. In the one case in which amputation was performed for infection rather than muscle necrosis, the lack of necrosis was correctly predicted with the scan. The limited results of this study indicate that the Tc-99m pyrophosphate scan allows the location of necrotic muscle to be predicted accurately and may therefore be a useful adjunct in determining the best level for ultimate amputation. Special caution is required in those cases in which muscle necrosis is due to acute causes (e.g., traumatic thrombosis) rather than chronic vascular disease.

Topics: Amputation, Surgical; Diphosphates; Extremities; Humans; Muscles; Muscular Diseases; Necrosis; Radionuclide Imaging; Regional Blood Flow; Retrospective Studies; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Animals; Antibodies, Monoclonal; Cyclosporins; Diphosphates; Graft Rejection; Heart; Heart Transplantation; Immunoglobulin Fab Fragments; Indium Radioisotopes; Male; Myocardium; Myosins; Necrosis; Radionuclide Imaging; Rats; Rats, Inbred Lew; Rats, Inbred SHR; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Adult; Antibodies, Monoclonal; Diphosphates; False Negative Reactions; False Positive Reactions; Female; Humans; Indium Radioisotopes; Male; Middle Aged; Myocardial Infarction; Myosins; Necrosis; Predictive Value of Tests; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors

The global myocardial extraction of lactate was measured in 13 halothane anesthetized dogs to assess the effect of electric countershock applied directly to the heart. Seven animals received two countershocks of 30 delivered joules each, while six animals were not shocked but were atrially paced to a rate of 190-200, both with and without occlusion of the vena cava to produce a mean arterial pressure of 40-50 mmHg. All animals had substantially positive lactate extraction in the baseline state (36 +/- 10% for countershock group vs. 41 +/- 3% for pacing group). Myocardial lactate extraction reached a markedly negative nadir 2.5 min after countershock (-19 +/- 15%), but returned toward normal by 6 min (10 +/- 6%). Lactate extraction was not significantly changed from baseline in the pacing group. The relationship between changes in regional myocardial blood flow (radiolabeled microspheres) and post-countershock myocardial damage (technetium pyrophosphate uptake) was assessed in six dogs shocked as above. Mean myocardial blood flow was increased minimally immediately after countershock (0.78 +/- 0.08 ml X min-1 X g-1 vs. 1.16 +/- 0.3), but there was no difference in blood flow between damaged and undamaged tissue at either time point. The epicardial-to-endocardial ratio of blood flow was unchanged after countershock (0.97 +/- 0.05 vs. 0.99 +/- 0.08). There was no relationship between myocardial damage and either the absolute amount of blood flow after countershock (r = -0.03) or the change in blood flow compared with the pre-shock period (r = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Circulation; Diphosphates; Dogs; Electric Countershock; Hemodynamics; Lactates; Lactic Acid; Microspheres; Myocardium; Necrosis; Regional Blood Flow; Technetium; Technetium Tc 99m Pyrophosphate

The management of an acutely ischemic extremity requires knowledge of the response of skeletal muscle (the largest component of the lower limb) to prolonged periods of complete normothermic ischemia. We have used the canine gracilis muscle model to evaluate the extent and distribution of ischemic necrosis after 3 and 5 hours of ischemia and 48 hours of reperfusion. Each muscle was cut into six slices, and the extent and distribution of postischemic necrosis identified by means of nitroblue tetrazolium staining and 99mTc pyrophosphate uptake. After 3, 4, and 5 hours of ischemia the extent of necrosis was 2.0% +/- 0.9%, 30.3% +/- 6.0%, and 90.1% +/- 3.5% (mean +/- SEM), respectively. A statistically significant correlation exists between the extent of necrosis and the uptake of 99mTc pyrophosphate uptake per gram of tissue (y = 1574.9x - 8.4, r = 0.84, p less than 0.001). Most necrosis was centrally located and found in the thickest portion of the muscle. We conclude that there is a graded response in the extent of skeletal muscle necrosis related to the length of ischemic stress rather than an "all-or-none" phenomenon. This central distribution of necrosis makes the usual external evaluation of ischemic damage clinically unreliable. In addition, since there was no enveloping fascia in this model, a compartment release alone may not prevent the development of skeletal muscle necrosis. This knowledge of the response of skeletal muscle to ischemia may lead to an improved clinical approach to an extremity suffering a prolonged ischemic insult.

Topics: Animals; Diphosphates; Dogs; Ischemia; Muscles; Necrosis; Nitroblue Tetrazolium; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors; Ultrasonography; Vascular Patency

Topics: Burns, Electric; Child, Preschool; Diphosphates; Humans; Male; Muscles; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Coronary Disease; Diphosphates; Electrocardiography; False Negative Reactions; Heart; Humans; Myocardium; Myoglobin; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

The Fab fragments of antimyosin antibodies, labeled with 99mTc, were used in the scintigraphic examination of 30 patients with myocardial infarction. The ability to detect necrosis and determine its extent from the antimyosin scan were compared with the results of quantitative regional wall motion analysis by contrast ventriculography at 10 to 14 days and 99mTc-pyrophosphate imaging. Antimyosin images recorded by planar and single photon-emission computed tomography (SPECT) delineated areas of myocardial necrosis in 27 of 30 patients (90%) compared with a 91% sensitivity of pyrophosphate in 21 of 23 patients. Infarct size was determined by both antimyosin and pyrophosphate SPECT images. Results by both techniques showed a significant correlation with computer-derived hypokinetic segment length (r = .79 for both, p = .002) and peak creatine kinase (r = .9 for both, p less than .01). Although sensitivity for and correlations with markers of necrosis were similar with both techniques, infarct size by pyrophosphate SPECT was 1.7 times larger than infarct size by antimyosin SPECT (p less than .01). Certain zones in the infarct area were differentially labeled; the nature and irreversibility of injury within these zones remains to be clarified.

Topics: Antibodies; Antibody Specificity; Cell Membrane Permeability; Diphosphates; Electrocardiography; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Myocardium; Myosins; Necrosis; Radionuclide Imaging; Technetium

This study examined the effect of exposures to hyperbaric oxygen on the development of the edema and necrosis of muscle that are associated with compartment syndromes that are complicated by hemorrhagic hypotension. A compartment syndrome (twenty millimeters of mercury for six hours) was induced by infusion of autologous plasma in the anterolateral compartment of the left hind limb of seven anesthetized dogs while the mean arterial blood pressure was maintained at sixty-five millimeters of mercury after 30 per cent loss of blood volume. These dogs were treated with hyperbaric oxygen (two atmospheres of pure oxygen) and were compared with six dogs that had an identical compartment syndrome and hypotensive condition but were not exposed to hyperbaric oxygen. Forty-eight hours later, edema was quantified by measuring the weights of the muscles (the pressurized muscle compared with the contralateral muscle), and necrosis of muscle was evaluated by measuring the uptake of technetium-99m stannous pyrophosphate. The ratio for edema was significantly (p = 0.01) greater in dogs that had not been exposed to hyperbaric oxygen (1.15 +/- 0.01) than in the dogs that had been treated with hyperbaric oxygen (1.01 +/- 0.03), and the ratio for necrosis of muscle was also significantly (p = 0.04) greater in dogs that had not had hyperbaric oxygen (1.96 +/- 0.41) than in those that had been treated with hyperbaric oxygen (1.05 +/- 0.11). Comparisons were also made with the muscles of four normal control dogs and separately with the muscles of six normotensive dogs that had an identical compartment syndrome and normal blood pressure and were not treated with hyperbaric oxygen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Compartment Syndromes; Diphosphates; Dogs; Edema; Hyperbaric Oxygenation; Necrosis; Radionuclide Imaging; Shock, Hemorrhagic; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Adolescent; Adult; Aged; Arm; Child; Diphosphates; Frostbite; Gangrene; Humans; Leg; Middle Aged; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Xeroradiography

Methods for evaluating cardiac myocyte necrosis utilizing antibodies specific for the heavy or light chains of cardiac myosin are reviewed. Cell death, associated with sarcolemmal disruption, results in the leakage of myosin light chains from the cytoplasm as well as the accessibility of myosin heavy chains to exogenous specific antibodies. Measurement of plasma light chain concentration has been useful in the diagnosis of myocardial infarction, though more recently, patients with congestive cardiomyopathy associated with an inflammatory infiltrate have been identified by an elevated plasma light chain concentration. The binding of myosin heavy chains to necrotic myocytes has been useful in the study of mechanisms of ischemic cell death in cell culture, in the diagnosis and quantification of myocardial infarction, both experimentally and clinically, and more recently in the study of experimental myocarditis and cardiac transplantation. It is hoped that these methods may evolve as useful clinical tools in the identification of those cardiomyopathy patients whose course is characterized by rapid myocyte loss.

Topics: Animals; Antibodies; Biopsy; Cardiomyopathies; Cell Survival; Creatine Kinase; Diphosphates; Heart; Heart Failure; Heart Transplantation; Humans; Immunoglobulin Fab Fragments; Indium; Isoenzymes; Mice; Myocardial Infarction; Myocardium; Myosins; Necrosis; Radioisotopes; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Thallium

Tc-99m pyrophosphate (PYP) can localize in an acute myocardial infarct and other extraosseous lesions, including soft tissue necrosis and severe cellular injury A case of Tc-99m PYP uptake in calf muscle necrosis following transfemoral cardiac catheterization is presented. This was incidentally detected on Tc-99m PYP imaging performed for an acute myocardial infarction. Repeat Tc-99m PYP imaging one month later was normal, implying resolution of the ischemic muscle necrosis.

Topics: Diphosphates; Humans; Leg; Male; Middle Aged; Muscles; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

The authors present comparative characteristics of different methods of assessing the size of myocardial infarction. They included among others radioimmunoassay of myoglobin and the activity of MB-CPK in the blood serum, ECG charting with the calculation of the ST-coefficient and 99mTc-pyrophosphate scanning of the myocardium. The most informative methods were determination of the serum content of myoglobin and of its hourly increment, monitoring of the total rise of the ST segment and ST coefficient on the cartogram and the measurement of the area of accumulation of radiopharmacologic preparations during myocardial scanning.

Topics: Aged; Creatine Kinase; Diphosphates; Drug Therapy, Combination; Electrocardiography; Female; Heart; Humans; Isoenzymes; Isosorbide Dinitrate; Male; Middle Aged; Myocardial Infarction; Myocardium; Myoglobin; Necrosis; Nitroglycerin; Prognosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors

To depict the three-dimensional distribution of 99mTc-pyrophosphate in the heart, emission computed tomography (ECT) was performed, following the conventional planar imaging, in 32 cases with suspected acute myocardial infarction (AMI). There were 23 cases with evidence of AMI, 7 with unstable angina (UA), and 2 with dilated cardiomyopathy (DCM). While the planar images showed discrete cardiac activity in only 11 of the 23 cases (48%) with AMI, the ECT images delineated focal myocardial uptake clearly in 20 of them (87%). On the other hand, the ECT images revealed cardiac blood-pool activity without significant myocardial uptake in all cases with UA and DCM in which the planar images showed diffuse activity. Thus, the ECT imaging of 99mTc-pyrophosphate seems to be a valuable technique for assessing the presence and localization of myocardial necrosis, especially in cases showing diffuse cardiac activity in the planar imaging.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Cardiomyopathies; Diagnosis, Differential; Diphosphates; Female; Heart; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Technetium; Technetium Tc 99m Pyrophosphate; Tomography, Emission-Computed; Tomography, X-Ray

Topics: Adult; Aged; Angina, Unstable; Diphosphates; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Right ventricular infarction is not uncommon in patients with inferior myocardial infarcts. Phase and amplitude analysis of equilibrium gated cardiac blood pool studies is useful in documenting right ventricular damage complicating left ventricular infarction. In 15 of 37 patients with acute inferior infarction, right ventricular extension of the infarct was demonstrated by this approach, complementing the findings of infarct avid imaging with Tc-99m pyrophosphate (Tc-99m PYP).

Topics: Aged; Diphosphates; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Animals; Coronary Circulation; Diatrizoate Meglumine; Diphosphates; Dogs; Indium; Myocardial Infarction; Myocardium; Necrosis; Radioisotopes; Technetium; Technetium Tc 99m Pyrophosphate; Thallium; Tomography, Emission-Computed

Scintigraphy with 99mTc-pyrophosphate during bicycle ergometry has been undertaken in 32 patients with myocardial infarction in the early phase of its healing. There were 3 scintigraphic investigations: one during bicycle ergometry and two control ones - before and the day after the test. The determination of changes in the degree of 99mTc-pyrophosphate accumulation under the influence of the exercise in patients with myocardial infarction in the early phase of its healing permitted the authors to detect several variants in the time course of scintigraphic values. Drop or rise of concentration of the labelled pyrophosphate at the height of the bicycle ergometry test compared to the data obtained prior to it are apparently due to changed bloodflow in the focus of lesion during exercise. Changes in the character and intensity of accumulation of the radiodrug after bicycle ergometry can be explained in the majority of cases by increase of metabolic disorders in the myocardium, supervening during the exercise, and in some patients, possibly, to sustained decrease of bloodflow in the affected area of the cardiac muscle.

Topics: Adult; Aged; Diphosphates; Exercise Test; Female; Heart; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors; Wound Healing

Topics: Angina Pectoris; Arteriosclerosis; Coronary Disease; Diagnosis, Differential; Diphosphates; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

To test the hypothesis that the relationship between infarct area (IA) and area at risk (AR) varies in different layers of the left ventricle (LV), we occluded the circumflex coronary artery for 48 h in 20 conscious dogs. AR was determined by postmortem coronary stereoarteriography, and infarct area by pathological examination. Both AR and IA were divided into four layers: posterior papillary muscle (PPM), subendocardium (Endo), midwall, and subepicardium (Epi) and quantified with planimetry. Hemodynamics and regional myocardial flow with tracer microspheres (7-10 micrometers diam) were measured before and after coronary occlusion. IA was closely correlated with AR for PPM (r = 0.96), Endo (r = 0.97), and Epi (r = 0.92). However, the slope of IA/AR for Endo (1.30 +/- 0.08) was significantly steeper (P less than 0.05) than that for Epi (0.89 +/- 0.11); furthermore, the intercepts at zero infarction for PPM (0.5 +/- 0.1% of LV), Endo (4.2 +/- 0.4%), and Epi (0.1 +/- 0.7%) were significantly different from each other. Regional blood flow measurements indicate that the differences in IA/AR in various layers reflected earlier and greater total collateral flow to the noninfarcted AR in the epicardium. Thus IA/AR for the entire LV is a composite representing separate IA/AR specific to various transmural layers of the LV. In addition, this study demonstrates that the lateral border zone between the IA and the AR is minimal (less than 3-5 mm) in the subendocardium and midwall layers of the left ventricle.

Topics: Animals; Diphosphates; Dogs; Heart Ventricles; Myocardial Infarction; Necrosis; Perfusion; Risk; Technetium; Technetium Tc 99m Pyrophosphate

The effect of transthoracic direct current countershock on the myocardium of 21 newborn piglets was studied. Myocardial damage was quantified by measuring the myocardial uptake of technetium-99m pyrophosphate injected 24 hours after countershock. Substantial myocardial damage occurred in animals given greater than 150 joules/kg but not at lower energy doses. Damage occurred in both ventricular free walls, but more frequently in the right ventricle. The epicardial half of the myocardium was more severely affected than the endocardial half. The relationship between myocardial damage and total countershock energy dose was well modeled by an exponential function. Transthoracic direct current countershock appears unlikely to cause myocardial damage in newborn piglets unless greatly elevated energy doses are employed.

Topics: Animals; Animals, Newborn; Diphosphates; Electric Countershock; Electrocardiography; Myocardium; Necrosis; Swine; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Animals; Blood Flow Velocity; Body Burden; Bone and Bones; Bone Resorption; Calcium; Cardiomyopathies; Diphosphates; Dogs; Drug Interactions; Humans; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Tissue Distribution

The incorporation rate of 99mTc-pyrophosphate into the myocardium was studied in 123 patients with acute myocardial infarction at different stages of the disease. The capacity of the damaged myocardium to accumulate the labelled pyrophosphate decreased with its healing. The accumulation character of the radiopharmacologic preparation also changed. The revealed phenomena are explained by the features of the 99mTc-pyrophosphate concentration mechanisms of the damaged areas of the myocardium. during the necrosis phase pyrophosphate is accumulated in the irreversibly damaged myocardial cells. The incorporation of 99mTc-pyrophosphate into the myocardium at the late stages of the disease are explained by both the presence of the necrotized cells in the myocardium and possible binding of the radiopharmacologic preparation to collagen.

Topics: Diphosphates; Female; Heart; Humans; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors

Topics: Coronary Disease; Diagnosis, Differential; Diphosphates; Heart Block; Humans; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

A survey is presented of research results of pyrophosphate myocardial scanning in 130 dogs and 150 patients with various myocardial lesions. The results of experiments in animals were immediately applied in clinical practice. The results showed that acute transmural myocardial lesions yielded practically in all instances positive scintigraphic findings. The findings in nontransmural infarctions were less convincing--they were positive in 60% of cases. Positive scintigraphic findings were also obtained in 80% of dogs with experimentally induced temporary ischaemia, and in 80% of dogs with experimentally induced dystrophy of the myocardium. In patients with angina pectoris positive findings were obtained in 1/3 of the cases, and in patients with cardiomyopathies, in 1/3 to 1/4 of the cases (in dependence on the etiology of the cardiomyopathy). It appears that 99mTc-PYP is a highly sensitive, but nonspecific, detector of myocardial lesions.

Topics: Angina Pectoris; Animals; Cardiomyopathies; Coronary Artery Bypass; Coronary Disease; Diphosphates; Dogs; Humans; Myocardial Infarction; Myocardium; Necrosis; Radionuclide Imaging; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Adult; Aged; Clinical Enzyme Tests; Diphosphates; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Myoglobin; Necrosis; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Arthritis, Rheumatoid; Cartilage, Articular; Collagen; Diphosphates; Humans; Hydroxyapatites; Joints; Necrosis; Osteoporosis

A case of radiation pneumonitis confirmed by tissue biopsy is presented with demonstration of increased uptake of 99mTc-pyrophosphate.

Topics: Adult; Diphosphates; Female; Humans; Lung Diseases; Lung Neoplasms; Necrosis; Radiation Injuries; Radionuclide Imaging; Radiotherapy; Technetium

Topics: Diphosphates; Humans; Myocardial Infarction; Myocardium; Necrosis; Radionuclide Imaging; Technetium

Topics: Adipose Tissue; Bone and Bones; Diphosphates; Fat Necrosis; Humans; Infant, Newborn; Infant, Newborn, Diseases; Necrosis; Radionuclide Imaging; Technetium

Topics: Child; Child, Preschool; Diphosphates; Female; Femur Neck; Hip; Humans; Legg-Calve-Perthes Disease; Male; Necrosis; Osteochondritis; Radionuclide Imaging; Technetium

Topics: Diphosphates; Humans; Liver Diseases; Male; Middle Aged; Myocardial Infarction; Necrosis; Radionuclide Imaging; Technetium

Topics: Animals; Diphosphates; Dogs; Myocardial Infarction; Myocardium; Necrosis

The present studies performed in experimental animals demonstrate that electrical direct current cardioversion can produce skeletal muscle damage and increased technetium-99m stannous pyrophosphate (99mTc-PYP) uptake; in experimental animals the electrically damaged skeletal muscle shows necrosis with extensive calcium deposition. In addition, the frequent administration of high energy cardioversion produces myocardial necrosis with calcium deposition, increased 99mTc-PYP myocardial uptake and a positive 99mTc-PYP myocardial scintigram. The data indicate that, if diagnostic 99mTc-PYP myocardial scintigraphy is contemplated after cardioversion, paddle placement should be slightly removed from the anteroposterior projection of the heart on the external chest wall to avoid possible subsequent confusion between increased myocardial and skeletal muscle uptake of 99mTc-PYP. If multiple high energy cardioversion episodes are necessary, myocardial necrosis resulting from electrical injury may occur and be responisble for increased myocardial uptake of 99mTc-PYP with a resultant positive 99mTc-PYP myocardial scintigram.

Topics: Animals; Diphosphates; Dogs; Electric Countershock; False Positive Reactions; Muscles; Muscular Diseases; Myocardial Infarction; Myocardium; Necrosis; Radionuclide Imaging; Technetium

The quantitative relationship between abnormalities seen on technetium-99m pyrophosphate (99mTc-PYP) infarct scintigrams and the size of the myocardial infarction is unclear. We evaluated two possible determinants of 99mTc-PYP accumulation: myocardial perfusion measured with 7-10 mu microspheres and the extent of necrosis determined histologically. Hemodynamics and myocardial perfusion to small segments of the left ventricle were measured prior to, 5-10 min, and 44-48 hours following sudden occlusion of the left anterior descending coronary artery in ten awake dogs. 99mTc-PYP was injected i.v. following the third injection of microspheres and the animals were killed 2 hours later. The important findings were as follows: 1) there is a close relationship between the extent of myocardial necrosis observed and the perfusion of segments 5-10 min following coronary occlusion; and 2) that segmental myocardial perfusion is an important determinant of 99mTc-PYP accumulation by myocardial segments which contain areas of necrosis. Although the present data preclude statistical analysis of the relationship between the level of necrosis in a segment and the accumulation of 99mTc-PYP by that segment, the two do not appear to be related, a finding which would discourage use of intensity of 99mTc-PYP images for infarct size. The distribution of an abnormality on the scintigram may provide an estimate of infarct size. However, the geometry of the infarct and the resolving power of the scanning equipment will significantly limit this in many clinical situations.

Topics: Animals; Coronary Circulation; Diphosphates; Disease Models, Animal; Dogs; Female; Male; Myocardial Infarction; Myocardium; Necrosis; Perfusion; Technetium

Topics: Animals; Bone Diseases; Bone Regeneration; Diphosphates; Dogs; Fractures, Spontaneous; Humans; Minerals; Necrosis; Osteogenesis; Pelvic Bones; Pyridoxine; Rabbits; Radiotherapy