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PubMed2002

Re-evaluation of phencyclidine low-affinity or "non-NMDA" binding sites.

TCP and its derivative gacyclidine (+/- GK11) are high-affinity non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors (NMDARs) and as such exhibit significant neuroprotective properties. These compounds also bind with a low affinity to binding sites whose pharmacological profiles are different from that of NMDARs. With the intention to develop new strategies of neuroprotection, we found it mandatory to investigate whether 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and gacyclidine low-affinity sites are similar. The effects of several drugs selective for either NMDARs or the [(3)H]TCP low-affinity site (or PCP(3) site) on (+), (-)[(3)H]GK11 and [(3)H]TCP specific binding were investigated. Competition experiments on cerebellum homogenates revealed substantial differences between the pharmacological profiles of the PCP(3) site and that of gacyclidine's enantiomers low-affinity sites. Under experimental conditions preventing the interaction of the radioligands with NMDARs, the autoradiographic study showed, however, that the distributions of both [(3)H]TCP and (-)[(3)H]GK11 specific binding were similar. The specific labelling was low and uniform in telencephalic structures, whereas in the cerebellum it was higher in the molecular than in the granular layer. Finally, the analysis of competition experiments performed on tissues slices demonstrated that PCP(3) selective ligands were unable to prevent [(3)H]TCP or (-)[(3)H]GK11 binding to "non-NMDA" binding sites. As a whole, our data suggest that: (1) the different pharmacological profiles of [(3)H]TCP and [(3)H]gacyclidine enantiomers on low-affinity sites are due to their selectivity for specific NMDARs subpopulations; (2) the pharmacological isolation of TCP and gacyclidine "non-NMDA" binding sites is the most appropriate way to further study the low-affinity component of their specific binding. Obtaining reliable and specific pharmacological tools for those binding sites is of particular interest, since it is likely that they play a substantial role in the low neurotoxicity, and therefore tolerability, of gacyclidine, a new neuroprotective drug currently evaluated in clinical trials for the treatment of brain and spinal cord injuries.

Animals↗
PubMed1999

Gestational exposure to chlorpyrifos: comparative distribution of trichloropyridinol in the fetus and dam.

Chlorpyrifos (O,O'-diethyl O-[3,5,6-trichloro-2-pyridyl] phosphorothionate) is a commonly used anticholinesterase insecticide, and therefore the potential for human exposure is high. The present time course and dose response studies were conducted to delineate the toxicokinetics of chlorpyrifos and its metabolites in the pregnant rat and fetus. Time-pregnant, Long-Evans rats were treated orally with chlorpyrifos during late gestation (Gestational Days 14-18). Following euthanasia the level of chlorpyrifos and its metabolites, chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol (TCP), were measured in both fetal and maternal brain and liver (limits of quantitation: 59.2, 28.8, and 14.0 ng/g tissue, respectively). In addition, cholinesterase inhibition was also measured in the same tissues for comparison. TCP was the only component detected. The highest level of TCP and the lowest level of cholinesterase activity showed the same time of peak effect: 5 h after the last dose. The concentration of TCP in the maternal liver was approximately fivefold higher than the TCP concentration in fetal liver, but, paradoxically, the concentration of TCP in the fetal brain was two- to fourfold higher than the TCP concentration in the maternal brain. The half-life of the TCP was identical in all tissues examined (12-15 h). These toxicokinetic results suggest that the fetal nervous system may be exposed to a higher concentration of chlorpyrifos than the maternal nervous system when the dam is orally exposed to chlorpyrifos during late gestation.

Animals↗
PubMed1998

Peroxidase-catalyzed oxidation of 2,4,6-trichlorophenol.

2,4,6-Trichlorophenol (TCP) is an environmental contaminant that is toxic, mutagenic, and carcinogenic. We have investigated peroxidase-catalyzed oxidation of TCP as an alternative pathway of TCP bioactivation using horseradish peroxidase (HRP) as a model peroxidase. TCP was shown to function as a reducing substarte for HRP as evidenced by TCP-dependent, HRP-catalyzed reduction of 5-phenyl-4-penten-1-yl hydroperoxide (PPHP) to its corresponding alcohol. In addition, TCP was shown to undergo hydroperoxide (H2O2, ethyl hydroperoxide, or PPHP)-dependent metabolism as evidenced by electronic absorption spectroscopic analysis of reaction mixtures. A single major product was detected by reverse phase HPLC and was identified as 2,6-dichloro-1,4-benzoquinone (2,6-dichloro-2, 5-cyclohexadiene-1,4-dione, CAS no. 697-91-6) on the basis of electronic absorption spectroscopy, mass spectrometry, and cochromatography with synthetic standard. In addition, HRP-catalyzed oxidation of TCP yielded EPR-detectable phenoxyl radical intermediates whose EPR spectrum consisted of a 1:2:1 triplet characterized by proton hyperfine coupling constants aH(3,5) = 2.35 gauss. Mechanisms for the hydroperoxide-dependent, HRP-catalyzed oxidation of TCP are proposed that are consistent with these results.

Catalysis↗
PubMed2002

Intramedullary anchoring strength of titanium rod with mixed beta-tricalcium phosphate and fibrin adhesive.

Histological and biomechanical studies were conducted in Japanese white rabbits to evaluate the effect of mixed beta-tricalcium phosphate (beta-TCP) and fibrin adhesive on bone formation around a titanium rod in femoral bone marrow. The animals received injections of fibrin adhesive with beta-TCP or hydroxyapatite into the femoral bone marrow from the distal end of the femur, where a titanium rod was inserted. Group I received fibrin adhesive only, group II received fibrin adhesive and hydroxyapatite (HA), and group III received fibrin adhesive and beta-TCP. On the examination of nondecalcified specimens, group III showed cross-bridging bone formation between beta-TCP particles at week 8, this being observed earlier than in group II. On mechanical evaluation, group III showed significant differences in maximum pull-out force at week 8, and in modulus of rigidity at week 24, compared with the other groups. On the examination of decalcified specimens, chronic inflammation was clearly identified in group I at week 8, and residual beta-TCP particles were found in group III at week 24. These results suggest that the mixture given to group III filled bone defects around the rod and promoted bone formation at a relatively early stage. Inflammation and delayed absorption of beta-TCP, which appeared to be a reaction of heterologous fibrins, caused delays in bone formation promoted by beta-TCP. Nevertheless, the use of fibrin adhesive appears to be a feasible method for loading powdered beta-TCP.

Analysis of Variance↗
PubMed1990

Vitamin K-dependent carboxylase: inhibitory action of polychlorinated phenols.

The compound 2,3,5,6-tetrachloropyridinol (TCP) is a known inhibitor of the rat liver vitamin K-dependent carboxylase. A series of chlorinated phenols was also assayed for their abilities to inhibit the carboxylase in vitro. One compound, 2,3,5,6-tetrachlorophenol, was as potent a carboxylase inhibitor as TCP (I50 = 5-10 microM). Four compounds with substituents in the 4 position exhibited I50 values 5-20 times greater than the identical structures with hydrogen in the 4 position. Tetrachloroanisol, the methyl ether of tetrachlorophenol, did not inhibit the reaction, and inhibition by 2,5-dichlorophenol, which has a pKa of 7.2, was pH dependent, suggesting that the anionic form of the phenol is the inhibitor. No other direct structure/function correlations were evident. Previous reports have shown that TCP inhibition of the carboxylase is not competitive versus vitamin K in vitro, but that in vivo antagonism by TCP can be reversed with vitamin K. Rats given 40 mg/kg TCP had decreased plasma prothrombin levels and increased amounts of liver microsomal prothrombin precursors, whereas rats injected with 1 mg vitamin K 24 hr before the TCP injection had normal levels of both. Vitamin K administration could not overcome completely the effects of 100 mg/kg TCP. Animals injected with TCP had increased levels of vitamin K 2,3-epoxide in the liver, which would be consistent with a partial inhibition of the microsomal vitamin K-epoxide reductase by this anticoagulant.

Animals↗
PubMed1978

Effects of halogenated antibacterials on the erythrocyte membrane.

The influence of halogenated antibacterials on membrane structure and function was investigated using the human erythrocyte membrane as a model. Measurements of hemolysis in isotonic solution, altered membrane permeability, and stabilization against hypotonic hemolysis resulting from exposure of erythrocytes to halogenated antibacterials served as criteria of membrane-related effects. The hemolytic potency of the compounds studied differed widely, decreasing in the order hexachlorophene (HCP) greater than 2,2'-methylenebis(3,5-dichlorophenol) (3,5-TCP) greater than 2,2'-methylenebis(3,4-dichlorophenol) (3,4-TCP) approximately equal to 2,2'-methylenebis(4,6-dichlorophenol) (4,6-TCP) greater than 2,2'-methylenebis(4-chlorophenol) (DCP) greater than 3,4'-tribromosalicylanilide (TBS) approximately equal to 3,3',4',5-tetrachlorosalicylanilide (TCSA). Each of the antibacterials tested stabilized the erythrocyte against hypotonic hemolysis, although there were marked differences in the concentrations required to afford maximum stabilization as well as in the extent of protection. The observed order of protective effectiveness was HCP greater than 3,4-TCP greater than 4,6-TCP greater than DCP approximately equal to TCS greater than TBS. As shown by measurements of the first-order rate constant for K+ efflux, the permeability of the erythrocyte membrane to K+ was increased upon exposure to the antibacterials, with the effect of HCP greater than 3,4-TCP greater than 4,6-TCP approximately equal to 3,4-TCP greater than DCP approximately equal to TCS greater than TBS. These results indicate that halogenated antibacterials are capable of perturbing mammalian membranes, a feature which may account in part for their mammalian toxicity.

Anti-Infective Agents↗
PubMed1984

Disposition of 1,2,3-trichloropropane in the Fischer 344 rat: conventional and physiological pharmacokinetics.

To investigate the disposition of 1,2,3-trichloropropane (TCP), [14C]-TCP was administered iv to male Fischer 344 rats. Unchanged TCP and total radiolabel were determined in tissues and excreta at varying intervals after administration. The compound was distributed and eliminated rapidly. Initial and terminal half-lives of unchanged TCP in the blood were 0.29 and 23 hr. Adipose tissue accumulated 37% of the dose within 15 min and retained more of the dose than any other tissue until 4 hr; most (69%) of the radiolabel in adipose tissue through 4 hr was unchanged TCP. After 4 hr, the liver contained the largest fraction of the dose, primarily as metabolites. Thus TCP disappeared from adipose tissue while metabolites appeared in liver and other tissues. Excretion was nearly complete (90% of the dose) in 24 hr and was predominantly via the urine (47% of the dose). Expiration was the only route by which unchanged TCP (5% of the dose) was excreted. In addition, 25% of the dose was expired as carbon dioxide. There were numerous other metabolites, none accounting for more than 10% of the dose. Nonvolatile metabolites were longer lived than the parent compound. On the basis of high water solubility, reaction with 2,4-dinitrofluorobenzene, and diminished radiolabel in bile of glycidol-treated rats, glutathione conjugation is suggested as an important metabolic route for TCP. A physiological pharmacokinetic model was developed to describe the time course of trichloropropane concentration in tissues. The model demonstrates the possibility of using physiological and pharmacokinetic data to predict concentration-time relations for toxic compounds.

Animals↗
PubMed1986

Molecular cloning and sequence analysis of a haploid expressed gene encoding t complex polypeptide 1.

The mouse t haplotypes show defects in spermatogenesis attributed to multiple loci on chromosome 17. We have cloned the gene for an abundant testicular germ cell protein, t complex polypeptide 1, which has a variant form in t haplotypes, TCP-1A. A cDNA clone, pB1.4, which hybridizes to a 19S mRNA that is abundant in haploid cells during mouse spermatogenesis, derives from the 3' end of the mRNA encoding TCP-1B. The Tcp-1 gene appears to be a member of a novel gene family and shows multiple changes between the predicted amino acid sequences of TCP-1B and TCP-1A. An additional Taq1 site is created by a T to C transition in the predicted open reading frame of the Tcp-1a gene. The resultant RFLP has allowed typing of the Tcp-1 gene cluster in 54 complete and partial t haplotype chromosomes. DNA sequence comparison of the Tcp-1 genes suggests that the t haplotype chromosome arose within the genus Mus more than one million years ago.

Animals↗
PubMed1991

Epitope differences in toxin-coregulated pili produced by classical and El Tor Vibrio cholerae O1.

A toxin-coregulated pilus (TCP), that is important for intestinal colonization of Vibrio cholerae O1, may be produced by vibrios of both classical and EI Tor biotypes. By comparing TCP produced by various strains of the two biotypes in immunoblotting and enzyme-linked immunosorbent assays (ELISA) using monoclonal antibodies (mAbs) and polyclonal antisera against TCP from classical vibrios, we have found biotype-related epitope differences in TCP. Our results indicate that TCP of classical strains has an epitope in the TcpA-subunit (20.5 kDa) that is missing in EI Tor TcpA, and an additional epitope that is more strongly expressed in classical TcpA. A polyclonal antiserum reacted strongly with TcpA from strains of both biotypes in immunoblotting suggesting both the presence of major shared TcpA epitopes and that the low or absent reactivity of EI Tor TcpA with the mAbs was not due to lower production of TcpA by EI Tor strains. Whereas all the TcpA-positive classical strains inhibited the binding of polyclonal antiserum and mAbs to solid phase-bound TCP-positive bacteria in an inhibition ELISA, practically no inhibition was observed with TcpA-positive EI Tor strains. This together with findings in immunoelectron microscopy studies that TCP 'bundles' were only detected on classical strains, suggest that TCP is poorly expressed on EI Tor vibrios.

Blotting, Western↗
PubMed2004

Final results of the ReoPro readministration registry.

Because of its potential for antigenicity, theoretical concerns related to readministration of abciximab have been raised. We conducted the ReoPro Readministration Registry to assess the efficacy and safety of abciximab readministration. A total of 1,342 patients who underwent percutaneous coronary intervention and who received abciximab for at least a second time were recruited. Safety end points were hypersensitivity reactions, major bleeding, and thrombocytopenia (TCP). Human antichimeric antibody (HACA) titers were determined before and after readministration. Procedural success was 98% and was not influenced by the number of courses of abciximab or the presence of HACA. There were no cases of anaphylaxis. There were 5 minor allergic reactions, none of which required termination of the infusion. Clinically significant bleeding occurred in 31 patients (2.3%), including 1 (0.07%) with intracranial hemorrhage. TCP (<100 x 10(9)/L) developed in 5% of patients; profound TCP (<20 x 10(9)/L) occurred in 2%. In patients who received abciximab within 1 month of a previous treatment (n = 115), the risk of developing TCP and profound TCP was 16.5% and 12.2%, respectively. Having a positive HACA before readministration was not correlated with adverse clinical outcomes or bleeding, but was associated with TCP (14.1% vs 4.4%, p = 0.002) and profound TCP (5.6% vs 1.6%, p = 0.036). Readministration of abciximab can be accomplished without severe allergic responses and with a bleeding and efficacy profile similar to first-time administration. However, the rate of severe and profound TCP is increased relative to first-time administration, particularly when the time between treatments is <30 days or when HACA is present.

Abciximab↗
PubMed2004

Structural characterization of room-temperature synthesized nano-sized beta-tricalcium phosphate.

A simple route for synthesizing nano-sized beta-tricalcium phosphate (beta-TCP) at room temperature has been developed in methanol solvent. The phase evolution from CaHPO4, intermediate amorphous calcium phosphate (ACP) phases (including ACP1 and ACP2 with different structures) to final beta-TCP with increasing aging time was observed. The formation of beta-TCP phase is favored due to the incorporation of carbonate which can suppress the transformation of ACP1 phase. High-resolution transmission electron microscopy image along [1-100] zone axis of beta-TCP reveals two types of lattice fringes (straight and wavy fringes) in beta-TCP structure due to structural imperfection. Furthermore, the observations of abnormal diffraction intensity and superlattice diffraction in selected-area diffraction patterns further confirm the chemical order-disorder characteristics in beta-TCP structure and can be used to elucidate the resorbability of beta-TCP in either in vivo or in vitro environment due to the imperfection in beta-TCP crystal.

Biocompatible Materials↗
PubMed2005

Preparation and characterization of porous beta-tricalcium phosphate/collagen composites with an integrated structure.

Porous beta-tricalcium phosphate (TCP)/collagen composites with different beta-TCP/collagen weight ratio were prepared. The influences of the preparation conditions on the microstructure of porous composite and the joint status of beta-TCP particles with collagen fibrils were characterized by X-ray diffractometer, scanning electron microscopy and transmission electron microscopy. The results showed: (1) an acid treatment could effectively disassemble collagen fibrils; (2) in the resulting porous composites, beta-TCP particles homogenously existed on the skeleton of the collagen fibril network and bonded tightly to both the fibrils and themselves. The tight bonding formation could be due to the reaction between Ca ions in the particles and carboxyl groups in collagen polypeptide chains and due to the reprecipitation of partially dissolved beta-TCP during synthesis. The tight bonding between beta-TCP particles and collagen fibrils in the composites demonstrated an integrated structure, which was reproducible when beta-TCP/collagen ratio ranged from 2 to 4. Such integrated structure would make significant contributions in reliably tailoring properties of the porous composites by varying beta-TCP content. In addition, the porous composites had large porosity (approximately 95%) and appropriate pore size (approximately 100 microm), showed no negative impact in cytotoxicity assay and complete bone tissue regeneration after 12 weeks in animal test.

Animals↗
PubMed2005

Delivery of orally supplemented alpha-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice.

The natural vitamin E tocotrienol (TCT) possesses biological properties not shared by tocopherols (TCP). Nanomolar alpha-TCT, not alpha-TCP, is potently neuroprotective (JBC 275:13049; 278:43508). Tocopherol-transport protein (TTP) represents the primary mechanism for maintaining normal alpha-TCP concentrations in plasma and extrahepatic tissues. TTP primarily transports alpha-TCP and has low affinity for alpha-TCT. There are no studies that have investigated tissue delivery of alpha-TCT when orally gavaged on a long-term basis. A long-term study was conducted to examine the effects of alpha-TCT or alpha-TCP supplementation, either alone or in combination, on tissue levels. Rats were maintained on a vitamin E-deficient diet and gavaged with alpha-TCT or alpha-TCP alone or in combination. Five generations of rats were studied over 60 weeks. TTP-deficient mice were supplemented with TCT and bred to examine tissue delivery of oral alpha-TCT. Orally supplemented alpha-TCT was effectively delivered to most tissues over time. When co-supplemented, alpha-TCP outcompeted alpha-TCT for transport systems delivering vitamin E to tissues. To evaluate the significance of TTP in alpha-TCT delivery to tissues, tissue levels of alpha-TCT in supplemented TTP-deficient mice were studied. alpha-TCT was transported to several vital organs in TTP-deficient mice. alpha-TCT restored fertility in TTP-deficient mice. In sum, orally supplemented alpha-TCT was successfully delivered to several vital organs. The transport efficiency of alpha-TCT to tissues may be maximized by eliminating the co-presence of alpha-TCP in the oral supplement. Examination of whether alpha-TCT may benefit humans suffering from neurological disorders because of congenital TTP deficiency is warranted.

Administration, Oral↗
PubMed2003

Ultrastructure of ceramic-bone interface using hydroxyapatite and beta-tricalcium phosphate ceramics and replacement mechanism of beta-tricalcium phosphate in bone.

Hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) are useful for grafting and augmentation of bone tissue. Observation by transmission electron microscopy (TEM) was done to investigate the ultrastructures at the interfaces between the biomaterials and the adjacent tissue, and osteogenesis around the biomaterials in the present study. HA and beta-TCP ceramics were used in disk forms which had macropores and micropores, and were implanted between the parietal bone and the cranial periosteum of rats. Specimens were prepared for observation at 4 and 8 weeks postoperatively. The microscopic results indicated that an intervening layer was present on the surface of HA, whereas it was not present on the surface of beta-TCP. A characteristic fibrillar structure was observed in the intervening layer between HA and bone under decalcification by HCl. In beta-TCP, in reticular structures observed close to the bone tissue by optical microscopy, calcification and sparse collagen fibers were interspersed among the granules of beta-TCP. In addition, close to the interface between beta-TCP and bone, many osteocytes with numerous processes were present. Some processes were elongated towards the interface. These results revealed the difference in the ultrastructures of the interfaces between HA and beta-TCP, and the dissolution mechanism of beta-TCP in bone.

Animals↗
PubMed2000

Characterization and immunogenicity of Vibrio cholerae ghosts expressing toxin-coregulated pili.

Bacterial ghosts are attractive for use as non-living vaccines and as carriers of heterologous antigens of vaccine relevance. Ghosts were prepared from Vibrio cholerae strains of O1 or O139 serogroup after growth under culture conditions, which favor or repress the production of toxin-coregulated pili (TCP). Immunoblotting confirmed the TCP status of these V. cholerae ghosts (VCG), which retained the cellular morphology and envelope sub-component profile of viable bacteria. Rabbits were immunized with VCGs prepared from O139 bacteria with TCP-positive or TCP-negative phenotypes and the resulting sera assayed for antibodies to lipopolysaccharide (LPS) and to TCP. Regardless of the TCP status of the VCG preparations used for immunization, all animals produced antibodies to LPS as demonstrated in bactericidal assays. These antibodies were probably responsible for the capacity of the antisera to confer passive immunity to challenge with the homologous O139 strain in the infant mouse cholera model (IMCM). Only following immunization with TCP-positive VCG, however, were antibodies to TCP generated, as judged by the potential of antisera to mediate protection against a challenge strain of heterologous serogroup.

Animals↗
PubMed2003

Bone augmentation osteogenesis using hydroxyapatite and beta-tricalcium phosphate blocks.

PURPOSE: In this study, we investigated the differences in osteogenesis and resorption between hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) implanted on the parietal bone of rats. MATERIALS AND METHODS: HA and beta-TCP were used in blocks with macropores and micropores. They were implanted between the parietal bone and the cranial periosteum in rats. Osteogenesis around the implanted materials was investigated histopathologically and histomorphometrically at 1, 2, 4, 8, and 24 weeks after surgery. RESULTS: At 2 weeks, osteogenesis from the parietal bone was observed around both materials, and new bone had attached directly to the surfaces of both materials. New bone grew into the pores of the upper regions of both materials with time. The beta-TCP block had a characteristic basophilic reticular structure in which the dissolution of the materials was observed close to the new bone. The HA blocks were stable for 24 weeks, whereas parts of the beta-TCP blocks were fractured and resorbed at 24 weeks. Histomorphometrically, the volume of new bone around HA was larger than that around beta-TCP. There was no remarkable change in the amount of remaining HA, but that of beta-TCP was decreased. CONCLUSION: HA blocks in this model are suitable for onlay grafts because of its stability and osteogenesis, beta-TCP is not stable. Therefore, when beta-TCP blocks are used for onlay grafts, the mechanical stress on the recipient site should be taken into consideration because of resorption and fracture.

Absorbable Implants↗
PubMed1989

Radiographic and microscopic evaluation of subperiosteally implanted blocks of hydrated and hardened alpha-tricalcium phosphate in rabbits.

Tissue response to preformed tricalcium phosphate (TCP) blocks prepared from alpha-tricalcium phosphate (alpha-TCP) powder by hydration and hardening at 80 degrees C was studied by implanting them subperiosteally on the buccal aspect of the mandible in rabbits. X-ray diffraction of the alpha-TCP powder showed a typical pattern of TCP, whereas a mixed pattern of TCP and hydroxylapatite was obtained after hydration and hardening. The radiographic findings at 4 weeks showed a tendency to bony union of the TCP block with the underlying bone. Microscopically, new bone that was being formed extensively from the underlying bone surface and filling the space between the block and bone at 4 weeks gradually changed into lamellar bone. There was no evidence of resorption of the TCP block throughout the experiment. The tissue response was essentially consistent with that to hydroxylapatite particles studied under similar conditions in our laboratory. It was concluded that the hydration and hardening of alpha-TCP powder may provide an implant block with a desirable contour that does not interfere with bone formation.

Animals↗
PubMed2000

Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging.

PURPOSE: Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. METHODS: MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. RESULTS: The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using (125)I seeds. The preset dose bounds of 100-150% to the prostate and 100-120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. CONCLUSIONS: Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for (125)I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Algorithms↗