Clinical and experimental observations of peripheral blood leukocytes and nucleated bone marrow cells after local irradiation.

AIM: Aim of the study was to observe the impact of bone marrow damage induced by local irradiation on leukopenia. METHODS: For the human study, five cancer patients received local radiation therapy. Bone marrow aspiration was conducted to measure nucleated cell count and 99mTc-Sc sulfur colloid ECT imaging was carried out to examine bone marrow function. For the animal study, fifty New Zealand white rabbits were divided into 3 groups: non-irradiated control group (N.=10), abdomen irradiation group (irradiation area did not cover bone marrow) (N.=20), chest irradiation group (irradiation area covered bone marrow) (N.=20). Nucleated cell counts were taken after confirming onset of leukopenia. RESULTS: Bone marrow of five patients proliferated normally. ECT imaging showed no abnormality in the pattern of red bone marrow distribution. Hematopoietic function was mildly active. CONCLUSION: Suppressed myeloproliferative function does not fully account for irradiation-induced leukopenia.

Enhanced homing permeability and retention of bone marrow stromal cells by noninvasive pulsed focused ultrasound.

Bone marrow stromal cells (BMSCs) have shown significant promise in the treatment of disease, but their therapeutic efficacy is often limited by inefficient homing of systemically administered cells, which results in low number of cells accumulating at sites of pathology. BMSC home to areas of inflammation where local expression of integrins and chemokine gradients is present. We demonstrated that nondestructive pulsed focused ultrasound (pFUS) exposures that emphasize the mechanical effects of ultrasound-tissue interactions induced local and transient elevations of chemoattractants (i.e., cytokines, integrins, and growth factors) in the murine kidney. pFUS-induced upregulation of cytokines occurred through approximately 1 day post-treatment and returned to contralateral kidney levels by day 3. This window of significant increases in cytokine expression was accompanied by local increases of other trophic factors and integrins that have been shown to promote BMSC homing. When BMSCs were intravenously administered following pFUS treatment to a single kidney, enhanced homing, permeability, and retention of BMSC was observed in the treated kidney versus the contralateral kidney. Histological analysis revealed up to eight times more BMSC in the peritubular regions of the treated kidneys on days 1 and 3 post-treatment. Furthermore, cytokine levels in pFUS-treated kidneys following BMSC administration were found to be similar to controls, suggesting modulation of cytokine levels by BMSC. pFUS could potentially improve cell-based therapies as a noninvasive modality to target homing by establishing local chemoattractant gradients and increasing expression of integrins to enhance tropism of cells toward treated tissues.

Chromosomal aberrations in the bone marrow cells of mice induced by accelerated (12)C(6+) ions.

The whole bodies of 6-week-old male Kun-Ming mice were exposed to different doses of (12)C(6+) ions or X-rays. Chromosomal aberrations of the bone marrow (gaps, terminal deletions and breaks, fragments, inter-chromosomal fusions and sister-chromatid union) were scored in metaphase 9h after exposure, corresponding to cells exposed in the G(2)-phase of the first mitosis cycle. Dose-response relationships for the frequency of chromosomal aberrations were plotted both by linear and linear-quadratic equations. The data showed that there was a dose-related increase in the frequency of chromosomal aberrations in all treated groups compared to controls. Linear-quadratic equations were a good fit for both radiation types. The compound theory of dual radiation action was applied to decipher the bigger curvature (D(2)) of the dose-response curves of X-rays compared to those of (12)C(6+) ions. Different distributions of the five types of aberrations and different degrees of homogeneity were found between (12)C(6+) ion and X-ray irradiation and the possible underlying mechanism for these phenomena were analyzed according to the differences in the spatial energy deposition of both types of radiation.

Nonmyeloablative conditioning regimens and bone marrow transplantation--some contemporary aspects.

The extensive use of bone marrow transplantation (BMT) in the treatment of a number of life threatening hematologic, oncologic and immunodeficiency disorders has come as a result of more than four decades of research and clinical experience. It is estimated that about 50,000 BMT per year are currently performed at more than 500 clinical centers all over the world. Total body irradiation (TBI) in combination with intensive chemotherapy (CT) proves to be a method without alternative in the preparation of patients with hematologic diseases for bone marrow or hematopoietic stem cells transplantation. Fractionated TBI is applied in myeloablative regimens where patients receive between 10 and 15 Gy. In the recent decade establishing the immunoreactivity of the graft lead to the introduction of nonmyeloablative conditioning regimens, including TBI, most often with a single dose of the order of 2 Gy received before transplantation. It is only in the last decade that the Bulgarian onco-radiologic community extended its knowledge and experience in the field of bone marrow transplantology. The first autologous BMT in Bulgaria was carried out in 1997, the first allogeneic BMT with conditioning TBI regimen--in 2002 and the first BMT with nonmyeloablative conditioning regimen including TBI with 2 Gy--in 2005. AIM OF The aim of the present review was to go over some aspects of the clinical experience that has been accumulated for the last ten years in the field of nonmyeloablative conditioning regimens and BMT. We also survey the basis for developing nonmyeloablative conditioning regimens, their aims and purposes, the main indications for their application, observed toxicity and therapeutic efficiency. The clinical experience gained in the last decade shows unambiguously that the BMT with conditioning "mini" TBI regimen, owing to the graft-versus-leukemia or graft-versus-tumor effect, is capable of achieving remission in patients with life threatening, conventional treatment-resistant hematologic, limphoproliferative disorders and some solid tumor.

[Feasibility of in vivo isotope labeled autologous mononuclear bone marrow cells monitoring post cardiac transplantation in a swine model of myocardial infarction].

OBJECTIVE: To observe in vivo stem cell distribution and viability after transplantation by noninvasive imaging of 18F-fluorodeoxyglucose (18F-FDG) labeled autologous mononuclear bone marrow cells. METHODS: Myocardial infarction was established in 8 swine by ligating left anterior descending coronary artery after anesthesia. Bone marrow (20 ml) was drawn through ileum. After isolation, mononuclear bone marrow cells were labeled by radionuclide 18F-FDG and intramyocardially injected into infarction region. Whole body planar scan and myocardial tomography scan were performed immediately, 1 h, 2 h, and 3 h post stem cell injection. Viability and stability of radionuclide labeled stem cells were determined at 3 h post labeling in vitro. RESULTS: The labeling efficiency was (67 +/- 14)%. Mean dose of radioactive in marrow cells was (32 +/- 7) MBq. Trypan blue staining showed in vitro viability was (95 +/- 3)% at 3 h post labeling. After intramyocardial injection, labeled mononuclear bone marrow cell retention rate in infarction region was (83 +/- 6)%, (49 +/- 8)%, (32 +/- 6)% and (24 +/- 5)% immediately, 1 h, 2 h, and 3 h post injection, respectively. CONCLUSIONS: Distribution and viability of stem cell after cardiac transplantation could be effective monitored by 18F-FDG labeled autologous mononuclear bone marrow cell technique in acute stage in this model.

Bone marrow stromal cell therapy improves femoral bone mineral density and mechanical strength in ovariectomized rats.

BACKGROUND: This study aimed to determine the influence of bone marrow stromal cells (BMSC) on the degree and sustainability of ovariectomy-induced bone loss. METHODS: Allogenic BMSC were injected into either the left or right femur of 15 ovariectomized rats (OVX). Saline was injected into the contralateral femur as a vehicle control. Five rats were killed at 8 weeks and 5 rats at 24 weeks. The other five OVX rats received serial injections 4 weeks after the first injection and were killed 24 weeks after the first injection. To confirm osteoporotic model, five rats received sham operation. Bone mineral density (BMD) was measured using dual-energy X-ray absorptometry. Mechanical properties were evaluated by three-point bending. RESULTS: The OVX rats showed significantly lower BMD compared with that of the sham operated rats. BMD at the femoral mid-shaft was significantly greater in the BMSC-injected bones compared with the control bones. At week 8, ultimate load and stiffness were also improved in the BMSC-injected bones compared with controls. At 24 weeks, the stiffness of control and BMSC-injected bones was statistically indistinguishable. The additional injection aided preservation of both BMD and mechanical properties. DISCUSSION: The present study suggests that bone strength may be improved by direct BMSC injection.

No effects of in vivo micro-CT radiation on structural parameters and bone marrow cells in proximal tibia of wistar rats detected after eight weekly scans.

Recently developed in vivo animal high-resolution micro-CT scanners offer the possibility to monitor longitudinal changes in bone microstructure of small rodents, but may impose high radiation doses that could damage bone tissue. The goal of this study was to determine the effects on the bone of 8 weeks of in vivo scanning of the proximal tibia in female Wistar rats. Eight weekly CT scans were made of the right proximal tibia of nine female, 30-week-old, retired-breeder, Wistar rats. Two weeks after the last weekly scan, a final scan was made. The left leg was only scanned during first and final measurements and served as a control. A two-way ANOVA with repeated measures was performed on the first and last measurements of left and right tibiae for six bone structural parameters. Bone marrow cells were flushed out and tested for cell viability. No significant difference was found between left and right for any of the bone structural parameters (p > 0.05). Structure model index and trabecular separation significantly changed as a result of aging, while none of the other parameters did. No significant difference was found between left and right in absolute and percentage number of cell viability. We did not find any indication that the applied scanning regime, in combination with the particular settings used, would affect the results of in vivo bone structural measurements in long-term studies using aged, female Wistar rats. However, careful consideration should be made when determining the number of scans, particularly when a different experimental design is used.

Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke.

OBJECTIVE: To evaluate the feasibility of monitoring the autologous mononuclear bone marrow (ABMMN) cells implanted into the brain after acute ischemic stroke by the technique of labeling with Tc-99m-HMPAO. CASE REPORT: A 37-year-old man presented with aphasia, right-side hypoesthesia, and right homonymous hemianopsia after an acute ischemic stroke of the left middle cerebral artery. He was included in an autologous bone marrow mononuclear cell-based therapy research protocol about the safety of intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Nine days after the stroke he received 3.0 x 10(7) ABMMN cells delivered into the left cerebral middle artery via a balloon catheter. Approximately 1% of these cells were labeled with 150 MBq (4 mCi) Tc-99m by incubation with hexamethylpropylene amine oxime (HMPAO). RESULTS: Brain perfusion images with Tc-99m ECD demonstrated hypoperfusion in the left temporal and parietal regions. The perfusion brain images were compared with tomographic views of the brain obtained 8 hours after ABMMN-labeled cell delivery, revealing intense accumulation of the ABMMN-labeled cells in the ipsilateral hemisphere. A whole-body scan was done and showed left brain, liver, and spleen uptake. CONCLUSIONS: Our results showed that Tc-99m HMPAO can be used to label ABMMN cells for in vivo cell visualization, and that brain SPECT imaging with labeled ABMMN cells is a feasible noninvasive method for studying the fate of transplanted cells in vivo. Additionally, our findings demonstrate the localization of these intra-arterially injected cells.

Short-term heart retention and distribution of intramyocardial delivered mesenchymal cells within necrotic or intact myocardium.

Cell therapy with bone marrow mesenchymal stem cells (BMSCs) is a new strategy for treating ischemic heart failure, but data concerning the distribution and retention of transplanted cells remain poor. We investigated the short-term myocardial retention of BMSCs when these cells are directly injected within necrotic or intact myocardium. 111Indium-oxine-labeled autologous BMSCs were injected within either 1-month-old infarction (n = 6) or normal myocardium (n = 6) from rats. Serial in vivo pinhole scintigraphy was scheduled during 1 week in order to track the implanted cells. The myocardial retention of BMSCs was definitely higher in myocardial infarction than in normal myocardial area (estimated percent retention at 2 h: 63 +/- 3% vs. 25 +/- 4%, p < 0.001) and the estimated cardiac retention values were unchanged in both groups along the 7 days of follow-up. On heart sections at day 7, labeled BMSCs were still around the injection site and appeared confined to the scarred tissue corresponding either to the infarct area or to the myocardium damaged by needle insertion. BMSCs have a higher retention when they are injected in necrotic than in normal myocardial areas and these cells appear to stay around the injection site for at least a 7-day period.

Patterns of red marrow in the adult femur.

PURPOSE: Conversion of red marrow (RM) to fatty marrow in the skeleton of the lower extremities begins at the distal end, ie, feet, and progresses proximally with distal bone marrow (ie, tibia) being converted more rapidly than proximal bone marrow (ie, femur). However, in an individual long bone, conversion begins in the diaphysis and progresses both distally and proximally (more rapidly toward the distal side). In a normal adult's femur, RM is present in the proximal one third or less. Reconversion of fatty marrow to RM is reported to occur in the reverse order of conversion. We assessed the frequency of various patterns of RM in the adult femur on In-111 leukocyte scans for a better understanding of the bone marrow regeneration process in individual long bones. METHODS: The patterns of marrow activity in the femur shown on In-111 leukocyte scans performed in 354 adults were divided into a) RM limited to the proximal one third or less, b) to the proximal two thirds, c) to the proximal one third and distal one third with no activity in the middle shaft, and d) in the entire femur. RESULTS: There were 207 patients with pattern A, 91 pattern B, 14 pattern C, and 42 pattern D. CONCLUSIONS: A considerably higher number of adults showed pattern B than pattern C. This suggests that regeneration of diaphyseal marrow precedes that of the distal marrow in an individual long bone or possibly that conversion of the latter precedes the former, which is different from that proposed in the literature.

Spatiotemporal control of gene expression in bone-marrow derived cells of the tumor microenvironment induced by MRI guided focused ultrasound.

The tumor microenvironment is an interesting target for anticancer therapies but modifying this compartment is challenging. Here, we demonstrate the feasibility of a gene therapy strategy that combined targeting to bone marrow-derived tumor microenvironment using genetically modified bone-marrow derived cells and control of transgene expression by local hyperthermia through a thermo-inducible promoter. Chimera were obtained by engraftment of bone marrow from transgenic mice expressing reporter genes under transcriptional control of heat shock promoter and inoculated sub-cutaneously with tumors cells. Heat shocks were applied at the tumor site using a water bath or magnetic resonance guided high intensity focused ultrasound device. Reporter gene expression was followed by bioluminescence and fluorescence imaging and immunohistochemistry. Bone marrow-derived cells expressing reporter genes were identified to be mainly tumor-associated macrophages. We thus provide the proof of concept for a gene therapy strategy that allows for spatiotemporal control of transgenes expression by macrophages targeted to the tumor microenvironment.

In Vivo Imaging and Tracking of Technetium-99m Labeled Bone Marrow Mesenchymal Stem Cells in Equine Tendinopathy.

Recent advances in the application of bone marrow mesenchymal stem cells (BMMSC) for the treatment of tendon and ligament injuries in the horse suggest improved outcome measures in both experimental and clinical studies. Although the BMMSC are implanted into the tendon lesion in large numbers (usually 10 - 20 million cells), only a relatively small number survive (<10%) although these can persist for up to 5 months after implantation. This appears to be a common observation in other species where BMMSC have been implanted into other tissues and it is important to understand when this loss occurs, how many survive the initial implantation process and whether the cells are cleared into other organs. Tracking the fate of the cells can be achieved by radiolabeling the BMMSC prior to implantation which allows non-invasive in vivo imaging of cell location and quantification of cell numbers. This protocol describes a cell labeling procedure that uses Technetium-99m (Tc-99m), and tracking of these cells following implantation into injured flexor tendons in horses. Tc-99m is a short-lived (t1/2 of 6.01 hr) isotope that emits gamma rays and can be internalized by cells in the presence of the lipophilic compound hexamethylpropyleneamine oxime (HMPAO). These properties make it ideal for use in nuclear medicine clinics for the diagnosis of many different diseases. The fate of the labeled cells can be followed in the short term (up to 36 hr) by gamma scintigraphy to quantify both the number of cells retained in the lesion and distribution of the cells into lungs, thyroid and other organs. This technique is adapted from the labeling of blood leukocytes and could be utilized to image implanted BMMSC in other organs.

Synchrotron radiation microtomography of bone engineered from bone marrow stromal cells.

Osteoprogenitor cells expanded in vitro and associated with porous ceramic scaffolds have been proposed as bone substitutes. Animal models have been developed to test the efficacy of various cell populations and scaffolds in promoting bone repair. Qualitative analysis of the new bone formed within the ceramic scaffold is relatively easy by conventional histology. On the other hand, quantitative data are difficult to obtain. X-ray computed microtomography was used as a possible experimental technique to obtain quantitative data on the three-dimensional structure of newly formed bone and of remaining scaffold in implants after 8 weeks in vivo. Measurements were performed at the European Synchrotron Radiation Facility on beamline ID19 with a spatial resolution of about 5 microm. This study clearly indicates the possibility of nondestructive quantitative analysis of bone-engineered constructs. The technique appears suitable to compare different scaffolds (and possibly different cell populations) with regard to bone formation efficiency and reabsorbability of biomaterials in the immunodeficient mouse model.

Tracing type 1 diabetic Tibet miniature pig's bone marrow mesenchymal stem cells in vitro by magnetic resonance imaging (1).

BACKGROUND: Traditional cell-tracking methods fail to meet the needs of preclinical or clinical research. Thus, the aim of the present study was to establish a new method of double labeling bone marrow mesenchymal stem cells (BMSCs) from type 1 diabetic (T1D) minipigs with super-paramagnetic iron oxide (SPIO) and enhanced green fluorescent protein (eGFP) and tracing them using MRI in vitro. METHODS: Isolated BMSCs from T1D minipigs were labeled with eGFP and different concentrations of SPIO. The effects of lentivirus (LV)-eGFP transfection and SPIO on the viability and growth curves of BMSCs were determined by Trypan blue exclusion, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry. Cellular ultrastructure was evaluated by transmission electron microscopy. Magnetic resonance imaging was used to evaluate BMSCs labeled with SPIO-eGFP complexes 6 weeks after labeling. RESULTS: Expression of eGFP in BMSCs peaked 96 h after transfection with LV-eGFP. Prussian blue staining revealed scattered blue granules in the cytoplasm of SPIO-labeled cells. Transmission electron microscopy revealed that the dense granules aggregated mainly in secondary lysosomes. On MRI, T2* -weighted imaging was far more sensitive for SPIO-labeled BMSCs than other image sequences 3 and 6 weeks after the cells had been labeled with SPIO-eGFP. CONCLUSIONS: We have developed a relatively simple and safe method for double labeling of BMSCs from T1D minipigs using SPIO and LV-eGFP and tracing them in vitro by MRI for 6 weeks.

[(18)F]FDG-PET standard uptake value as a metabolic predictor of bone marrow response to radiation: impact on acute and late hematological toxicity in cervical cancer patients treated with chemoradiation therapy.

PURPOSE: To quantify the relationship between bone marrow (BM) response to radiation and radiation dose by using (18)F-labeled fluorodeoxyglucose positron emission tomography [(18)F]FDG-PET standard uptake values (SUV) and to correlate these findings with hematological toxicity (HT) in cervical cancer (CC) patients treated with chemoradiation therapy (CRT). METHODS AND MATERIALS: Seventeen women with a diagnosis of CC were treated with standard doses of CRT. All patients underwent pre- and post-therapy [(18)F]FDG-PET/computed tomography (CT). Hemograms were obtained before and during treatment and 3 months after treatment and at last follow-up. Pelvic bone was autosegmented as total bone marrow (BMTOT). Active bone marrow (BMACT) was contoured based on SUV greater than the mean SUV of BMTOT. The volumes (V) of each region receiving 10, 20, 30, and 40 Gy (V10, V20, V30, and V40, respectively) were calculated. Metabolic volume histograms and voxel SUV map response graphs were created. Relative changes in SUV before and after therapy were calculated by separating SUV voxels into radiation therapy dose ranges of 5 Gy. The relationships among SUV decrease, radiation dose, and HT were investigated using multiple regression models. RESULTS: Mean relative pre-post-therapy SUV reductions in BMTOT and BMACT were 27% and 38%, respectively. BMACT volume was significantly reduced after treatment (from 651.5 to 231.6 cm(3), respectively; P<.0001). BMACT V30 was significantly correlated with a reduction in BMACT SUV (R(2), 0.14; P<.001). The reduction in BMACT SUV significantly correlated with reduction in white blood cells (WBCs) at 3 months post-treatment (R(2), 0.27; P=.04) and at last follow-up (R(2), 0.25; P=.04). Different dosimetric parameters of BMTOT and BMACT correlated with long-term hematological outcome. CONCLUSIONS: The volumes of BMTOT and BMACT that are exposed to even relatively low doses of radiation are associated with a decrease in WBC counts following CRT. The loss in proliferative BM SUV uptake translates into low WBC nadirs after treatment. These results suggest the potential of intensity modulated radiation therapy to spare BMTOT to reduce long-term hematological toxicity.

Differential effects of exercise on tibial shaft marrow density in young female athletes.

CONTEXT: Increased mechanical loading can promote the preferential differentiation of bone marrow mesenchymal stem cells to osteoblastogenesis, but it is not known whether long-term bone strength-enhancing exercise in humans can reduce marrow adiposity. OBJECTIVE: Our objective was to examine whether bone marrow density (MaD), as an estimate of marrow adiposity 1) differs between young female athletes with contrasting loading histories and bone strengths and 2) is an independent predictor of bone strength at the weight-bearing tibia. DESIGN: Mid-tibial MaD, cortical area (CoA), total area, medullary area, strength strain index (SSI), and cortical volumetric bone mineral density (vBMD) (total, endocortical, midcortical, and pericortical) was assessed using peripheral quantitative computed tomography in 179 female athletes involved in both impact and nonimpact loading sports and 41 controls aged 17-40 years. RESULTS: As we have previously reported CoA, total area, and SSI were 16% to 24% greater in the impact group compared with the controls (all P < .001) and 12% to 18% greater than in the nonimpact group (all P < .001). The impact group also had 0.5% higher MaD than the nonimpact and control groups (both P < .05). Regression analysis further showed that midtibial MaD was significantly associated with SSI, CoA, endocortical vBMD, and pericortical vBMD (P < .05) in all women combined, after adjusting for age, bone length, loading groups, medullary area, muscle cross-sectional area, and percent fat. CONCLUSION: In young female athletes, tibial bone MaD was associated with loading history and was an independent predictor of tibial bone strength. These findings suggest that an exercise-induced increase in bone strength may be mediated via reduced bone marrow adiposity and consequently increased osteoblastogenesis.

Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging.

PURPOSE: Given that proliferating hematopoietic stem cells are especially radiosensitive, the bone marrow is a potential organ at risk, particularly with the use of concurrent chemotherapy and radiotherapy. Existing data on bone marrow distribution have been determined from the weight and visual appearance of the marrow in cadavers. 18F-fluoro-L-deoxythymidine concentrates in bone marrow, and we used its intensity on positron emission tomography imaging to quantify the location of the proliferating bone marrow. METHODS AND MATERIALS: The 18F-fluoro-L-deoxythymidine positron emission/computed tomography scans performed at the Peter MacCallum Cancer Centre between 2006 and 2009 on adult cancer patients were analyzed. At a minimum, the scans included the mid-skull through the proximal femurs. A software program developed at our institution was used to calculate the percentage of administered activity in 11 separately defined bony regions. RESULTS: The study population consisted of 13 patients, 6 of whom were men. Their median age was 61 years. Of the 13 patients, 9 had lung cancer, 2 had colon cancer, and 1 each had melanoma and leiomyosarcoma; 6 had received previous, but not recent, chemotherapy. The mean percentage of proliferating bone marrow by anatomic site was 2.9%±2.1% at the skull, 1.9%±1.2% at the proximal humeri, 2.9%±1.3% at the sternum, 8.8%±4.7% at the ribs and clavicles, 3.8%±0.9% at the scapulas, 4.3%±1.6% at the cervical spine, 19.9%±2.6% at the thoracic spine, 16.6%±2.2% at the lumbar spine, 9.2%±2.3% at the sacrum, 25.3%±4.9% at the pelvis, and 4.5%±2.5% at the proximal femurs. CONCLUSION: Our modern estimates of bone marrow distribution in actual cancer patients using molecular imaging of the proliferating marrow provide updated data for optimizing normal tissue sparing during external beam radiotherapy planning.

3'-deoxy-3'-[¹8F]fluorothymidine PET quantification of bone marrow response to radiation dose.

PURPOSE: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans. METHODS AND MATERIALS: Pre- and post-Week 1 treatment [(18)F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [(18)F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients. RESULTS: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs. CONCLUSIONS: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [(18)F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [(18)F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity.

Enhanced bone formation by marrow-derived endothelial and osteogenic cell transplantation.

Bone marrow-derived osteogenic cells can regenerate bone tissuesin vivo. The aim of the present study is to determine whether the cotransplantation of bone marrow-derived endothelial-like cells (BMECs) enhances bone regeneration by bone marrow-derived osteogenic cell (BMOC) transplantation in osseous defects. Canine bone marrow cells were differentiated separately into BMECs and BMOCs. Using apatite-coated poly(lactide-co-glycolide)/hydroxyapatite composite scaffolds as cell delivery vehicles, BMOCs were transplanted with or without BMECs into critical-sized calvarial defects in immunodeficient mice. Histological analyses, microcomputed tomography, and soft X-ray were performed to assess mineralized bone formation at 8 weeks. Cotransplantation of BMECs and BMOCs resulted in greater bone formation than transplantation of BMOCs alone. There was a significant (p < 0.05) increase in bone formation area following cotransplantation (30.8% +/- 2.5%), compared with transplantation of BMOCs alone (15.3% +/- 1.9%). These results demonstrate that the cotransplantation of BMECs enhances bone regeneration mediated by BMOC transplantation in osseous defects.