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PubMed1993

Biogenesis and regulation of the Vibrio cholerae toxin-coregulated pilus: analogies to other virulence factor secretory systems.

Biogenesis of the toxin-coregulated pilus (TCP) of Vibrio cholerae 01 is essential for successful bacterial colonization of the small intestine. Pilus assembly requires the products of at least seven genes located on the chromosome adjacent to the pilin-encoding gene, tcpA. Previously reported TnphoA insertions in the TCP-assembly-deficient V. cholerae strains, KP2.21 and KP4.2, were isolated from the chromosome for further analysis. Nucleotide sequencing of the tcpE::phoA and tcpF::phoA fusions and corresponding clones of the region containing the intact genes revealed the presence of two open reading frames (ORFs) of 340 and 338 amino acids, designated TcpE and TcpF, respectively. The partial sequence of an ORF downstream from the TcpF coding sequence was determined to correspond to the global virulence regulator, ToxT. Proteins corresponding to the observed ORFs were visualized with the T7 promoter/RNA polymerase expression system. Computer-generated alignment algorithms predict that a homology exists between TcpE and the Klebsiella pneumoniae pullulanase secretion proteins PulD and PulF, the Xanthomonas campestris extracellular enzyme secretion factor XpsF, the Bacillus subtilis DNA competence protein ComG-ORF2, and the Yersinia enterocolitica Yop secretion determinant YscC. These observations provide a model to investigate further the relationship between the secretion mechanisms utilized by these seemingly diverse virulence determinants. Additionally, an extreme C-terminal segment of TcpE shows striking homology to the transmembrane segment of the eukaryotic integrin beta-1 chain, which could imply a role for TcpE in not only TCP secretion, but also host cell interaction.

Amino Acid Sequence↗
PubMed2005

Nanostructured calcium phosphates for biomedical applications: novel synthesis and characterization.

Materials play a key role in several biomedical applications, and it is imperative that both the materials and biological aspects are clearly understood for attaining a successful biological outcome. This paper illustrates our approach to implement calcium phosphates as gene delivery agents. Calcium phosphates (CaP) belong to the family of biocompatible apatites and there are several CaP phases, the most ubiquitous being hydroxyapatite (HAp, Ca(10)(PO(4))(6)(OH)(2). Other CaP structures include brushite (B, CaHPO(4).2H(2)O) and tricalcium phosphate (TCP, Ca(3)(PO(4))(2)). Several low and high temperature approaches have been reported for synthesizing HAp and brushite, while TCP is primarily synthesized using high temperature methods. Novel low temperature chemical methods have been developed by us to synthesize nanostructured HAp, brushite and TCP phases. The new low temperature approach results in the formation of stoichiometric and nanosized HAp under physiological conditions. Moreover, the synthesis methods were designed to be biocompatible with biological systems such as cells, DNA and proteins so that the CaP structures can be studied for gene delivery. The use of HAp type CaP phases for gene delivery is well known but to our knowledge, other forms of CaP have not been studied for gene delivery due to the lack of a biocompatible synthesis method. In addition to the biocompatible synthesis of CaP structures, we have also performed ion substitution that would provide us the appropriate tools to study the DNA-to-particle interactions and assess how these ionic substitutions would affect the level of DNA uptake by the cell and then its release to the cell nucleus. Substitution of calcium by 14% magnesium results in the formation of crystalline ( approximately 20 mum) brushite platelets that remains stable at pH 7.5. Further substitution results in unique nanostructured spherical morphologies of brushite from which rosette shaped high specific surface area ( approximately 200 m(2)/g) nanocrystals ( approximately 80 nm) of beta-TCMP phase can be grown. The novelty lies in the formation of stable phases of HAp, brushite and beta-TCMP under physiological conditions making them potential candidates for use as carriers for non-viral gene delivery or more generally in biological systems. The resultant nanocrystalline phosphates have been characterized for their structure, morphology, thermal stability, and composition. Results of the in vitro transfection are also described.

3T3 Cells↗
PubMed2003

Fracture of Bilok interference screws on insertion during anterior cruciate ligament reconstruction.

New femoral and tibial interference screws for use during anterior cruciate ligament (ACL) reconstruction have been developed using a composite of poly-L-lactic acid (PLLA) and tricalcium phosphate (TCP). The combination is described as having better incorporation than standard bioabsorbable screws with no loss of mass during incorporation and without the brittle nature associated with conventional TCP implants. However, the screw can fracture during insertion, leaving the distal third inside the femoral or tibial tunnel, making extraction and revision difficult. This is a report of 2 cases of PLLA-TCP screw breakage, 1 occurring in the femoral tunnel and 1 occurring in the tibial tunnel.

Absorbable Implants↗
PubMed2004

Phenotypic expression of bone-related genes in osteoblasts grown on calcium phosphate ceramics with different phase compositions.

Calcium phosphate ceramics with different hydroxyapatite (HA) and tricalcium phosphate (TCP) ratios have different chemical properties. Does the difference in phase composition affect osteoblast behavior? In this study, osteoblasts were cultured on 4 kinds of calcium phosphate ceramics, i.e. pure (HA), HT1 (HA/TCP, 70/30), HT2 (HA/TCP, 35/65), and pure TCP. Cell proliferation of SaOS-2 cells together with bone-related genes' mRNA expression and protein production in osteoblasts cultured on different calcium phosphate ceramics were detected at different time points. Data suggested that cell proliferation rate on TCP ceramics was lower than that on the other substrates tested. Generally, mRNA expressions for osteonectin and osteocalcin were similar among the four kinds of ceramics in most circumstances, whereas at six days, alkaline phosphatase mRNA expression was higher on HA and HT1 surfaces than on the other two materials. Collagen I mRNA expression was also affected by the phase composition of substrates. Osteocalcin and bone sialoprotein production in SaOS-2 cells was very similar no matter which ceramic surface the cells were grown upon. This study revealed that calcium phosphate ceramics substrate could support osteoblast growth and bone-related gene expression and its gene expression pattern explained the basis of the biocompatibility and bioactivity for calcium phosphate ceramics.

Animals↗
PubMed2005

Modulation of porosity in apatitic cements by the use of alpha-tricalcium phosphate-calcium sulphate dihydrate mixtures.

Calcium phosphate bone cements are injectable biomaterials that are being used in dental and orthopaedic applications through minimally invasive surgery techniques. Nowadays, apatitic bone cements based on alpha-tricalcium phosphate (alpha-TCP) are of special interest due to their self-setting behaviour when mixed with an aqueous liquid phase. In this study, a new method to improve osteointegration of alpha-TCP-based cements is presented. This method consists in the modification of the cement's powder phase with different amounts of calcium sulphate dihydrate (CSD). The resulting hardening properties of the new biphasic cements are a combination between the progressive hardening due to the main alpha-TCP reactant and the progressive dissolution of the CSD phase, which render a porous material. It was observed that the maximum compressive strength of Biocement-H (45 MPa) decreased as the amount of CSD increased in the cement powder mixture ( approximately 30 MPa for 25 wt% of CSD). It was also observed that after complete dissolution of the CSD phase a porous apatitic structure appears with a mechanical compressive strength suitable for cancellous bone applications (10 MPa).

Apatites↗
PubMed2005

Biocompatibility and resorption of a brushite calcium phosphate cement.

A hydraulic calcium phosphate cement with beta-tricalcium phosphate (TCP) granules embedded in a matrix of dicalcium phosphate dihydrate (DCPD) was implanted in experimentally created defects in sheep. One type of defect consisted of a drill hole in the medial femoral condyle. The other, partial metaphyseal defect was located in the proximal aspect of the tibia plateau and was stabilized using a 3.5 mm T-plate. The bone samples of 2 animals each per group were harvested after 2, 4, 6 and 8 weeks. Samples were evaluated for cement resorption and signs of immediate reaction, such as inflammation, caused by the cement setting in situ. Differences regarding these aspects were assessed for both types of defects using macroscopical, radiological, histological and histomorphometrical evaluations. In both defects the brushite matrix was resorbed faster than the beta-TCP granules. The resorption front was followed directly by a front of new bone formation, in which residual beta-TCP granules were embedded. Cement resorption occurred through (i) extracellular liquid dissolution with cement disintegration and particle formation, and (ii) phagocytosis of the cement particles through macrophages. Signs of inflammation or immunologic response leading to delayed new bone formation were not noticed at any time. Cement degradation and new bone formation occurred slightly faster in the femur defects.

Absorbable Implants↗
PubMed2005

Matrix-mediated retention of adipogenic differentiation potential by human adult bone marrow-derived mesenchymal stem cells during ex vivo expansion.

Recently, cell-based approaches utilizing adipogenic progenitor cells for fat tissue engineering have been developed and reported to have success in promoting in vivo adipogenesis and the repair of defect sites. For autologous applications, human bone marrow-derived mesenchymal stem cells (MSCs) have been suggested as a potential cell source for adipose tissue engineering applications due to their ability to be isolated and ex vivo expanded from adult bone marrow aspirates and their versatility for pluripotent differentiation into various mesenchymal lineages including adipogenic. Due to the relatively low frequency of MSCs present within bone marrow, extensive ex vivo expansion of these cells is necessary to obtain therapeutic cell populations for tissue engineering strategies. Currently, utilization of MSCs for adipose tissue engineering is limited due to the attenuation of their adipogenic differentiation potential following extensive ex vivo expansion on conventional tissue culture plastic (TCP) substrates. In the present study, the ability of a denatured collagen type I (DC) matrix to preserve MSC adipogenic potential during ex vivo expansion was examined. Adipocyte-related markers and functions were examined in vitro in response to adipogenic culture conditions for 21 days in comparison to early passage MSCs and late passage MSCs ex vivo expanded on TCP. The results demonstrated significant preservation of the ability of late passage MSCs ex vivo expanded on the DC matrix to express adipogenic markers (fatty acid-binding protein-4, lipoprotein lipase, acyl-CoA synthetase, adipsin, facilitative glucose transporter-4, and accumulation of lipids) similar to the early passage cells and in contrast to late passage MSCs expanded on TCP. The ability of the DC matrix to preserve adipocyte-related markers and functions of MSCs following extensive ex vivo expansion represents a novel culture technique to expand functional adipogenic progenitors for tissue engineering applications.

Adipocytes↗
PubMed2005

Influence of three-dimensional scaffold on the expression of osteogenic differentiation markers by human dermal fibroblasts.

Current research in the field of tissue engineering utilizes biomaterial scaffolds, cells, and growth factors for the creation of a functional, biologically active tissue. This study examined the effect of two commercially available, three-dimensional scaffolds, ultraporous beta-tricalcium phosphate ceramics (beta-TCP, Vitoss) and open-celled poly(lactic acid) foams (OPLA, Drilac), on the osteogenic differentiation potential of human dermal fibroblasts. Serum-free, chemically-defined medium containing the metabolic factor 1alpha,25-dihydroxyvitamin D3 was used to promote an osteogenic phenotype in these cells. Osteoblast differentiation was assessed using PCR and immunohistochemical methods to detect gene and protein expression for the osteoblast markers alkaline phosphatase, osteopontin, and osteocalcin. Dermal fibroblasts cultured on beta-TCP scaffolds in chemically-defined medium with vitamin D3 exhibited up-regulated gene and protein expression compared to cells cultured on OPLA scaffolds. These results suggest that Vitoss (beta-TCP) scaffolds seeded with dermal fibroblasts and maintained in chemically-defined medium with vitamin D3 are better suited for bone tissue engineering applications than Drilac (OPLA) foams.

Biomarkers↗
PubMed2006

An in vivo study of a growth-factor enhanced, cell free, two-layered collagen-tricalcium phosphate in deep osteochondral defects.

Focal osteochondral defects are still a challenging problem in joint surgery. We have developed a two-layered implant consisting of a basal porous beta-tricalcium phosphate (TCP) for bone reconstruction and a superficial fibrous collagen type I/III layer for cartilage regeneration. Fifty-four osteochondral defects in the trochlear groove of 27 Göttinger Minipigs were created and either left untreated, treated with the implant alone, or the implant augmented with an additional growth factor mixture, which was assumed to stimulate cell and tissue differentiation. Follow-up was 6, 12 and 52 weeks with n=6 for each group. The repair tissue was evaluated for its gross appearance and biomechanical properties. Histological sections were semi-quantitatively scored for their histomorphological structure. Treatment with the two-layered implant improved defect filling and subchondral bone repair at 6 and 12 weeks follow-up. The TCP was replaced by cancellous bone at 52 weeks. Cartilage repair tissue mainly consisted of fibrocartilage and showed a moderate cell density up to the joint surface. Growth factor treatment improved the mechanical and histomorphological properties of the cartilage repair tissue at 12, but not at 52 weeks postoperatively. In conclusion, the two-layered collagen-TCP implant augmented with chondroinductive growth factors seems a promising new option for the treatment of deep osteochondral defects in joint surgery.

Animals↗
PubMed2006

In vitro and in vivo reactivity of porous, electrosprayed calcium phosphate coatings.

The dissolution and/or precipitation behaviour of porous calcium phosphate (CaP) coatings, deposited using electrostatic spray deposition (ESD), was investigated (a) in vitro after soaking in simulated body fluid (SBF) for several time periods (2, 4, 8, and 12 weeks), and (b) in vivo after subcutaneous implantation of CaP-coated implants in the back of goats for identical time periods. Physical and chemical properties of coatings were characterized before and after in vitro/vivo testing by means of scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, and energy dispersive spectroscopy. Moreover, part of the explants was prepared for light microscopical evaluation of the tissue response. In vitro, all apatitic ESD-coatings induced the formation of homogeneous and adherent CaP precipitation layers. Amorphous CaP, however, displayed a delayed precipitation of poorly adherent CaP layers, whereas heterogeneous calcification was observed on top of beta-TCP-coated substrates, indicating that beta-TCP and amorphous CaP coatings exhibit a poor ability of inducing calcification in SBF as compared to crystalline apatitic coatings. In vivo, no adverse tissue reactions (toxic effects/inflammatory cells) were observed using light microscopy, and all coatings became surrounded by a dense, fibrous tissue capsule after implantation. All ESD-coatings degraded gradually at a dissolution rate depending on the chemical phase (order of relative solubility: amorphous CaP approximately carbonate apatite>beta-TCP>carbonated hydroxyapatite), thereby enabling synthesis of CaP coatings with a tailored degradation rate.

Animals↗
PubMed2006

Repair of long intercalated rib defects using porous beta-tricalcium phosphate cylinders containing recombinant human bone morphogenetic protein-2 in dogs.

A new method to repair rib defects with biomaterials containing recombinant human bone morphogenetic protein-2 (rhBMP-2) is presented in this report. We had reported previously the successful regeneration of bony rib defects by placing a short chain of small beta-tricalcium phosphate (beta-TCP) cylinders on the intact periosteum. The multi-cylinder implants were ineffective in promoting rib repair when the periosteum was absent. By adding rhBMP-2 to the beta-TCP cylinders, we were able to promote rib bone regeneration in the presence or absence of the periosteum. The osteogenic capacity of the rhBMP-2/beta-TCP composite implant and the time required to complete regeneration were evaluated in a canine model. An 8cm long section of rib bone, including the periosteum, was removed and replaced with a chain of the rhBMP-2/beta-TCP cylinders. At 6 weeks after implantation, the ribs were restored to their original configuration and mechanical strength. The multi-cylinder beta-TCP implants were degraded and replaced by new bone in 12 weeks. This new degradable bone-inducing implant material has significant clinical potential for rib repair.

Absorbable Implants↗
PubMed2005

Sequential UV-biological degradation of chlorophenols.

The sequential UV-biological degradation of a mixture of 4-chlorophenol (CP), 2,4-dichlorophenol (DCP), 2,4,6-trichlorophenol (TCP), and pentachlorophenol (PCP) was first tested with each pollutant supplied at an initial concentration of 50 mg l(-1). Under these conditions, the chlorophenols were photodegraded in the following order of removal rate: PCP>TCP>DCP>CP with only CP and DCP remaining after 40 h of irradiation. The remaining CP (41 mg l(-1)) and DCP (13 mg l(-1)) were then completely removed by biological treatment with an activated sludge mixed culture. Biodegradation did not occur in similar tests conducted with a non-irradiated mixture due to the high microbial toxicity of the solution. UV treatment lead to a significant reduction of the phytotoxicity to Lipedium sativum but no further reduction of phytotoxicity was observed after biological treatment. Evidence was found that the pollutants were partially photodegraded into toxic and non-biodegradable products. When the pollutants were tested individually (initial concentration of 50 mg l(-1)), PCP, TCP, DCP, 4-CP were photodegraded according to first order kinetic model (r2>99) with half-lives of 2.2, 3.3, 5.7, and 54 h, respectively. The photoproducts were subsequently biodegraded. This study illustrates the potential of UV as pre-treatment for biological treatment in order to remove toxicity and enhance the biodegradability of organic contaminants. However, it also shows that UV treatment must be carefully optimized to avoid the formation of toxic and/or recalcitrant photoproducts and results from studies conducted on single contaminants cannot be extrapolated to mixtures.

Biodegradation, Environmental↗
PubMed2004

Compaction, compression and drug release characteristics of xanthan gum pellets of different compositions.

Compaction and compression of xanthan gum (XG) pellets were evaluated and drug release from tablets made of pellets was characterised. Three formulations were prepared by extrusion-spheronisation and included, among other excipients, diclofenac sodium (Dic Na), at 10% (w/w); xanthan gum, at 16% (w/w); and one of three different fillers (lactose monohydrated (LAC), tribasic calcium phosphate (TCP) and beta-cyclodextrin (beta-CD)), at 16% (w/w). Five hundred milligrams of pellets (fraction 1000-1400microm) were compacted in a single punch press at maximum punch pressure of 125MPa using flat-faced punches (diameter of 1.00cm). Physical properties of pellets and tablets were analysed. Dissolution was performed according to the USP paddle method. Pellets showed close compressibility degrees (49.27% LAC; 51.32% TCP; and 50.48% beta-CD) but densified differently (3.57% LAC; 14.84% TCP; 3.26% beta-CD). Permanent deformation and densification were the relevant mechanisms of compression. Fragmentation was regarded as non-existent. The release behaviour of tablets made of pellets comprising LAC or beta-CD was anomalous having diffusional exponent (n) values of 0.706 and 0.625, respectively. Drug diffusion and erosion were competing mechanisms of drug release from those tablets.

Calcium Phosphates↗
PubMed2006

Comparison of human alveolar osteoblasts cultured on polymer-ceramic composite scaffolds and tissue culture plates.

The effects of medical grade polycaprolactone-tricalcium phosphate (mPCL-TCP) (80:20) scaffolds on primary human alveolar osteoblasts (AOs) were compared with standard tissue-culture plates. Of the seeded AOs, 70% adhered to and proliferated on the scaffold surface and within open and interconnected pores; they formed multi-layered sheets and collagen fibers with uniform distribution within 28 days. Elevation of alkaline phosphatase activity occurred in scaffold-cell constructs independent of osteogenic induction. AO proliferation rate increased and significant decrease in calcium concentration of the medium for both scaffolds and plates under induction conditions were seen. mPCL-TCP scaffolds significantly influenced the AO expression pattern of osterix and osteocalcin (OCN). Osteogenic induction down-regulated OCN at both RNA and protein level on scaffolds (3D) by day 7, and up-regulated OCN in cell-culture plates (2D) by day 14, but OCN levels on scaffolds were higher than on cell-culture plates. Immunocytochemical signals for type I collagen, osteopontin and osteocalcin were detected at the outer parts of scaffold-cell constructs. More mineral nodules were found in induced than in non-induced constructs. Only induced 2D cultures showed nodule formation. mPCL-TCP scaffolds appear to stimulate osteogenesis in vitro by activating a cellular response in AO's to form mineralized tissue. There is a fundamental difference between culturing AOs on 2D and 3D environments that should be considered when studying osteogenesis in vitro.

Alkaline Phosphatase↗
PubMed2006

Enhancement of drug affinity for cell membranes by conjugation with lipoamino acids II. Experimental and computational evidence using biomembrane models.

Lipoamino acids (LAAs) are promoieties able to enhance the amphiphilicity of drugs, facilitating their interaction with cell membranes. Experimental and computational studies were carried out on two series of lipophilic amide conjugates between a model drug (tranylcypromine, TCP) and LAA or alkanoic acids containing a short, medium or long alkyl side chain (C-4 to C-16). The effects of these compounds were evaluated by monolayer surface tension analysis and differential scanning calorimetry using dimyristoylphosphatidylcholine monolayers and liposomes as biomembrane models. The experimental results were related to independent calculations to determine partition coefficient and blood-brain partitioning. The comparison of TCP-LAA conjugates with the related series of TCP alkanoyl amides confirmed that the ability to interact with the biomembrane models is not due to the mere increase of lipophilicity, but mainly to the amphipatic nature and the kind of LAA residue.

Amino Acids↗
PubMed2004

Application of the linear-quadratic model to combined modality radiotherapy.

PURPOSE: Methods of performing dosimetry for a combined modality radiotherapy (CMRT) consisting of a targeted radionuclide therapy (TRT) and separately delivered external beam therapy (EBT) have been established using the biologically effective dose (BED). However, a concurrent delivery of the two therapies may influence the radiobiologic effect of the treatment resulting from interaction between the therapies, and this situation has been modeled to assess the likely consequences of this regime. METHODS AND MATERIALS: A general form of the linear-quadratic model with a dose protraction factor was applied to concurrent delivery of EBT and TRT. Contributions to total BED from intra- and intermodality effects were calculated, and parameter values varied to determine conditions under which the intermodality contributions were likely to be most significant. A Poisson model of tumor control probability (TCP) was used to assess the predicted effect of concurrent delivery on treatment outcome. RESULTS: In general, over a wide range of parameter values, the effect of intermodality interactions in CMRT is small, increasing total BED delivered to tumor by approximately 1%, and producing a negligible increase in TCP. Synergistic effects could be greater in normal tissues if high doses were received from both therapies, with intermodality terms increasing total BED delivered by approximately 6% in the general case, and by approximately 18% for the case of slow repair in the spinal cord. A significant synergistic effect was predicted between EBT and I-125 seed therapy of the prostate when values of alpha/beta = 1.2 Gy, alpha = 0.026 Gy, mu = 0.36 h(-1) and N(0) = 138 clonogens were used, with TCP increasing from approximately 0.5 to 0.6. CONCLUSIONS: Under most clinical conditions, the relative temporal delivery of these two therapies is unlikely to significantly influence the overall radiobiologic effect to tumor at the cellular level. Synergistic effects may, however, be more significant in normal tissues and for tumors with low values of alpha/beta and alpha.

Combined Modality Therapy↗
PubMed2004

Dosimetry and radiobiologic model comparison of IMRT and 3D conformal radiotherapy in treatment of carcinoma of the prostate.

INTRODUCTION: Intensity-modulated radiotherapy (IMRT) has introduced novel dosimetry that often features increased dose heterogeneity to target and normal structures. This raises questions of the biologic effects of IMRT compared to conventional treatment. We compared dosimetry and radiobiologic model predictions of tumor control probability (TCP) and normal tissue complication probability (NTCP) for prostate cancer patients planned for IMRT as opposed to standardized three-dimensional conformal radiotherapy (3DCRT). METHODS AND MATERIALS: Segmented multileaf collimator IMRT treatment plans for 32 prostate cancer patients were compared to 3DCRT plans for the same patients. Twenty-two received local-field irradiation (LFI), and 10 received extended-field irradiation (EFI) that included pelvic lymph nodes. For LFI, IMRT was planned for delivery of 2 Gy minimum dose to the prostate (> or =99% volume coverage) for 35 fractions. The 3DCRT plans, characterized by more homogenous dose to the target, were designed according to a different protocol to deliver 2 Gy to the center of the prostate for 37 fractions. Mean total dose from 35 fractions of IMRT was equal to mean total dose from 37 fractions of 3DCRT. For EFI, both IMRT and 3DCRT were planned for 2 Gy per fraction to a total dose of 50 Gy to prostate and pelvic lymph nodes, followed by 2 Gy per fraction to 20 Gy to the prostate alone. Treatment dose for EFI-IMRT was defined as minimum dose to the target, whereas for EFI-3DCRT, it was defined as dose to the center of the prostate. TCP was calculated for the prostate in the linear-quadratic model for two choices of alpha/beta. NTCP was calculated with the Lyman model for organs at risk, using Kutcher-Burman dose-volume histogram reduction with Emami parameters. RESULTS AND CONCLUSIONS: Dose to the prostate, expressed as mean +/- standard deviation, was 74.7 +/- 1.1 Gy for IMRT vs. 74.6 +/- 0.3 Gy for 3D for the LFI plans, and 74.8 +/- 0.6 Gy for IMRT vs. 71.5 +/- 0.6 Gy for 3D for the EFI plans. For the studied protocols, TCP was greater for IMRT than for 3D across the full range of target sensitivity, for both localized- and extended-field irradiation. For LFI, this was due to the smaller number of fractions (35 vs. 37) used for IMRT, and for EFI, this was due to the greater mean dose for IMRT, compared to 3D. For all organs, mean NTCP tended to be lower for IMRT than for 3D, although NTCP values were very small for both 3D and IMRT. Differences were statistically significant for rectum (LFI and EFI), bladder (EFI), and bowel (EFI). For both LFI and EFI, the calculated NTCPs qualitatively agreed with early published clinical data comparing genitourinary and gastrointestinal complications of IMRT and 3D. Present calculations support the hypothesis that accurately delivered IMRT for prostate cancer can limit dose to normal tissue by reducing treatment margins relative to conventional 3D planning, to allow a reduction in complication rate spanning several sensitive structures while maintaining or increasing tumor control probability.

Algorithms↗
PubMed2004

Predicting the effect of temporal variations in PO2 on tumor radiosensitivity.

PURPOSE: Tumor hypoxia is associated with less effective radiation-mediated cell killing, increased metastatic potential, and poorer prognosis. Transient variations in hypoxia, with characteristic periodicity on the order of 1 to 10 min, have been observed in animal models. This article explores the effect of these temporal variations in PO(2) on the oxygen enhancement ratio, effective radiation dose to the tumor, and tumor control probability. METHODS AND MATERIALS: PO(2) over a 50-60 min period was determined at multiple sites in rat fibrosarcomas, 9L gliomas, and R3230Ac mammary adenocarcinomas. Using a correlation derived from the data of Elkind et al. (1965), PO(2) data are converted into oxygen enhancement ratios (OERs.) A tumor is assumed to consist of 10(3)-10(4) independent oxygenation subvolumes, each with a randomly chosen starting point on the OER-time curve. The effect of temporal variations in OER is examined for three cases: conventionally fractionated external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS) and intraoperative radiotherapy (IORT). The oxygen effective dose (OED) for a subvolume is calculated from the dose to that subvolume modified by the OER. In turn, the distribution of OED for a tumor is analyzed for each treatment case and representative tumor control probabilities (TCPs) calculated. RESULTS: Oxygen enhancement ratio varied from 1 to 3 over the range of PO(2) measured in this study. Mean OER ranged from 1.6 to 2.6, and the variation in OER vs. time was greater with decreasing PO(2). In EBRT, the standard deviation in OED was small, <2%. In contrast, the standard deviation in OED was much higher for both SRS and IORT, typically ranging from 3 to 6%, with the greatest variation at the lowest PO(2)s. Compared with a tumor with equal mean OED and uniform PO(2), TCP was minimally poorer for either EBRT or well-oxygenated tumors. However, for both SRS and IORT, temporal variations in more hypoxic tumors can produce a significant decrease in TCP. CONCLUSION: Temporal variations in tumor PO(2) can produce significant variations OER, particularly at low PO(2), resulting in decreased TCP for hypofractionated treatment regimens.

Algorithms↗