Perioperative PET/CT lymphoscintigraphy and fluorescent real-time imaging for sentinel lymph node mapping in early staged colon cancer.

PURPOSE: Using current optical imaging techniques and gamma imaging modalities, perioperative sentinel lymph node (SLN) identification in colon cancer can be difficult when the SLN is located near the primary tumour or beneath a thick layer of (fat) tissue. Sentinel lymph node mapping using PET/CT lymphoscintigraphy combined with real-time visualization of the SLN using near-infrared imaging has shown promising results in several types of cancer and may facilitate the successful identification of the number and location of the SLN in early colon cancer. METHODS: Clinical feasibility of PET/CT lymphoscintigraphy using preoperative endoscopically injected [89Zr]Zr-Nanocoll and intraoperative injection of the near-infrared (NIR) tracer Indocyanine Green (ICG) was evaluated in ten early colon cancer patients. Three preoperative PET/CT scans and an additional ex vivo scan of the specimen were performed after submucosal injection of [89Zr]Zr-Nanocoll. All SLNs and other lymph nodes underwent extensive pathological examination for metastases. A histopathological proven lymph node visible at preoperative PET/CT and identified at PET/CT of the specimen was defined as SLN. RESULTS: A total of 27 SLNs were harvested in seven out of eight patients with successful injection of both tracers. In one patient no SLNs were assigned preoperatively. In two patients injection of [89Zr]Zr-Nanocoll failed due to incorrect needle positioning. Twenty-one (78%) SLNs were found intraoperatively using NIR-imaging. Eleven of the 27 (41%) SLNs were located near the primary tumour (< 2 cm). Those six SLNs not found intraoperatively with NIR-imaging were all located close to the tumour. In all seven patients at least one SLN could be assigned at preoperative imaging 24 h after tracer administration. One SLN contained metastases detected by immunohistochemistry. No metastases were found in the non-SLNs. CONCLUSIONS: This study shows the potential of preoperative PET/CT lymphoscintigraphy to inform the surgeon about the number and location of SLNs in patients with early colon cancer. The additional use of NIR-imaging allows for intraoperative identification of these SLNs which are invisible with conventional white light imaging. Further research is necessary to improve and simplify the technique. We recommend perioperative SLN identification using a preoperative lymphoscintigraphy scan just before surgery approximately 24 h after injection. Additionally a postoperative scan of the specimen combined with intraoperative real-time NIR-imaging should be performed.

Pharmaceutical preparation of oxygen-15 labelled molecular oxygen and carbon monoxide gasses in a hospital setting.

BACKGROUND: Clinical positron emission tomography (PET) requires safe and effective PET radiopharmaceuticals. Tracers used for measuring oxygen consumption and blood volume are [(15)O]O(2) and [(15)O]CO, respectively. In general, these oxygen-15 labelled tracers are produced using a cyclotron that accelerates deuterons onto a target filled with (14)N(2) containing a trace of oxygen. In recent years, cyclotrons have been developed that only are capable of accelerating protons. The purpose of this study was to validate and assess such a cyclotron for production and administration of oxygen-15 labelled gasses in an hospital setting. METHODS: An RDS111 cyclotron (Siemens-CTI, Knoxville, USA) was validated for bolus production of [(15)O]O(2) and [(15)O]CO gasses. In addition, equipment was developed to administer these tracers to patients. RESULTS: Both [(15)O]O(2) and [(15)O]CO gasses could be produced in sufficient amounts, whilst meeting European Pharmacopeia requirements. Although produced oxygen-15 gasses contained a minor level of (11)C contamination, in clinical studies it was possible to correct for this contamination by delayed blood counting. CONCLUSION: An 11 MeV proton cyclotron combined with an in-house developed gas delivery system allows for the production and administration of sufficient amounts of [(15)O]-gasses for routine clinical PET studies in an hospital setting.

Effect of fluid loading with saline or colloids on pulmonary permeability, oedema and lung injury score after cardiac and major vascular surgery.

BACKGROUND: The optimal type of fluid for treating hypovolaemia without evoking pulmonary oedema is still unclear, particularly in the presence of pulmonary vascular injury, as may occur after cardiac and major vascular surgery. METHODS: In a single-centre, prospective, single-blinded clinical trial 67 mechanically ventilated patients were randomly assigned to receive saline, gelatin 4%, HES 6% or albumin 5%, according to a 90 min fluid loading protocol with target central venous pressure of 13 and pulmonary capillary wedge pressure of 15 mm Hg, within 3 h after cardiac or major vascular surgery. Before and after the protocol, we recorded haemodynamics and ventilatory variables and took chest radiographs. The pulmonary vascular injury was evaluated using the 67Ga-transferrin pulmonary leak index (PLI) and extravascular lung water (EVLW). Plasma colloid osmotic pressure (COP) was determined and the lung injury score (LIS) was calculated. RESULTS: More saline was infused than colloid solutions (P<0.005). The COP increased in the colloid groups and decreased in patients receiving saline. Cardiac output increased more in the colloid groups. At baseline, PLI and EVLW were above normal in 60 and 30% of the patients, with no changes after fluid loading, except for a greater PLI decrease in HES than in gelatin-loaded patients. The oxygenation ratio improved in all groups. In the colloid groups, the LIS increased, because of a decrease in total respiratory compliance, probably associated with an increase in intrathoracic plasma volume. CONCLUSIONS: Provided that fluid overloading is prevented, the type of fluid used for volume loading does not affect pulmonary permeability and oedema, in patients with acute lung injury after cardiac or major vascular surgery, except for HES that may ameliorate increased permeability. During fluid loading, changes in LIS (and respiratory compliance) do not represent changes in pulmonary permeability or oedema.

Pulmonary abnormalities after cardiac surgery are better explained by atelectasis than by increased permeability oedema.

BACKGROUND: Cardiac surgery can be complicated by pulmonary abnormalities, but it is unclear how various manifestations interrelate. METHODS: A prospective study in the intensive care unit was performed on 26 mechanically ventilated patients without cardiac failure within 3 h after elective cardiac surgery involving cardiopulmonary bypass. Oedema (extravascular lung water, EVLW) was measured by the thermal-dye technique and permeability by a dual radionuclide technique, yielding a pulmonary leak index (PLI). Radiographic, mechanical and gas exchange features were used to calculate the lung injury score (LIS), ranging between 0 and 4. Evidence for left lower lobe atelectasis was obtained from plain radiographs. The plasma colloid osmotic pressure (COP) was measured by an oncometer. RESULTS: The EVLW (normal, <7 ml/kg) was elevated in 36% of patients and the PLI (normal, <14.1 x 10(-3)/min) in 44%, but the variables did not interrelate directly. Patients with a supranormal EVLW had a lower COP than patients with normal EVLW. The duration of mechanical ventilation was prolonged in patients (20%) with EVLW > 10 ml/kg. There was no difference in EVLW and PLI in patients with LIS < 1 and LIS > 1 (31% of patients). In patients with radiographic evidence for atelectasis (46%), the positive end-expiratory pressure and inspiratory O2 fraction to maintain oxygenation were higher than in those without. CONCLUSIONS: After cardiac surgery, mild pulmonary oedema is relatively common, even in the absence of high filling pressures, and is mainly attributable to a low COP, irrespective of increased permeability in about one-half of patients. It may prolong mechanical ventilation at EVLW > 10 ml/kg. However, pulmonary radiographic and ventilatory abnormalities may result, at least in part, from atelectasis rather than increased permeability oedema.

Evaluation of pulmonary nodules: comparison of a prototype dual crystal (LSO/NAI) dual head coincidence camera and full ring positron emission tomography (PET).

PURPOSE: To determine the concordance of a prototype dual head coincidence camera (LSO-PS) and full ring PET (BGO-PET) using (18)F-fluorodeoxyglucose (FDG) in the evaluation of pulmonary nodules (PNs). MATERIALS AND METHODS: Patients referred for evaluation of < or =3 PNs (< or =3 cm diameter) were prospectively studied on the same day with both BGO-PET and LSO-PS. Imaging was performed at 60 and 120 min after injection of 370MBq FDG, respectively. Images were independently interpreted by four observers with each observer blinded to the other modality for the same patient. Lesions were scored in terms of relative intensity versus background. Non-attenuation corrected (nonAC) BGO-PET was used as the reference test. RESULTS: Forty-seven patients with 54 PNs (mean diameter 1.7 cm, S.D. 0.7) were included. Twelve nodules were in the < or =1.0 cm - 27 in the 1.1-2.0 cm - and 15 in the 2.1-3.0 cm range. Interobserver agreement was similar for both FDG imaging modalities. Using a sensitive assessment strategy with LSO-PS (> or = faint intensity deemed positive), there was a 97% (38/39, 95%CI 87-100%) concordance with BGO-PET and one false positive case with LSO-PS. Conservative reading (moderate or intense intensity deemed positive) resulted in a 92% (36/39, 95%CI 80-97%) concordance with BGO-PET, without false positives. The only lesion missed by LSO-PS using both assessment strategies involved a nodule 1.5 cm diameter that demonstrated moderate increased FDG uptake on BGO-PET. CONCLUSION: Depending on the test positivity criteria, LSO-PS demonstrates a high concordance (92-97%) with nonAC BGO-PET for the characterization of pulmonary nodules.

Optimization of attenuation correction for positron emission tomography studies of thorax and pelvis using count-based transmission scans.

The quality of thorax and pelvis transmission scans and therefore of attenuation correction in PET depends on patient thickness and transmission rod source strength. The purpose of the present study was to assess the feasibility of using count-based transmission scans, thereby guaranteeing more consistent image quality and more precise quantification than with fixed transmission scan duration. First, the relation between noise equivalent counts (NEC) of 10 min calibration transmission scans and rod source activity was determined over a period of 1.5 years. Second, the relation between transmission scan counts and uniform phantom diameter was studied numerically, determining the relative contribution of counts from lines of response passing through the phantom as compared with the total number of counts. Finally, the relation between patient weight and transmission scan duration was determined for 35 patients, who were scanned at the level of thorax or pelvis. After installation of new rod sources, the NEC of transmission scans first increased slightly (5%) with decreasing rod source activity and after 3 months decreased with a rate of 2-3% per month. The numerical simulation showed that the number of transmission scan counts from lines of response passing through the phantom increased with phantom diameter up to 7 cm. For phantoms larger than 7 cm, the number of these counts decreased at approximately the same rate as the total number of transmission scan counts. Patient data confirmed that the total number of transmission scan counts decreased with increasing patient weight with about 0.5% kg(-1). It can be concluded that count-based transmission scans compensate for radioactive decay of the rod sources. With count-based transmission scans, rod sources can be used for up to 1.5 years at the cost of a 50% increased transmission scan duration. For phantoms with diameters of more than 7 cm and for patients scanned at the level of thorax or pelvis, use of count-based transmission scans is feasible and results in statistically more consistent transmission scans as compared with fixed transmission scan duration.

Nuclear imaging is more sensitive for the detection of viable myocardium than dobutamine echocardiography.

Intact perfusion, preserved metabolism of free fatty acids and glucose, and the presence of contractile reserve have been used as markers of viable myocardium. However, not all viable myocardium may exhibit all these characteristics. Accordingly, these features were evaluated in patients with chronic coronary artery disease and left ventricular dysfunction. Fourteen patients with chronic ischaemic heart disease and depressed left ventricular function (LVEF 34+/-10%) perfusion was evaluated by early resting 201Tl single photon emission computed tomography (SPECT), fatty acid utilization by 15-p-[123I]iodophenyl-3-(R,S)-methylpentadecanoic acid SPECT, glucose utilization by 2-[18F]fluoro-2-deoxy-D-glucose SPECT and contractile reserve (CR) by dobutamine echocardiography. The comparison of the different modalities was restricted to akinetic or dyskinetic myocardium as assessed by resting 2-dimensional echocardiography. For all techniques a 13-segment model was used. Sixty-four of 182 segments (35%) showed akinesia or dyskinesia. Intact perfusion was found in 33/64 (52%) segments. Fatty acid utilization was maintained in 38/64 (59%) segments and glucose utilization was maintained in 38/64 (59%) segments. CR was present in significantly fewer segments: 21 of 64 (33%) (P<0.01 vs glucose and fatty acid utilization). In the 21 segments with preserved CR, perfusion was intact in 16/21 (76%) segments, fatty acid utilization in 19/21 (90%) segments and glucose utilization was preserved in all (100%) segments. Conversely, in the 43 segments without CR, 17 segments (40%) showed intact perfusion, 19 segments (44%) preserved fatty acid utilization and 17 (40%) still showed preserved glucose utilization. Disagreement in segments between the viability markers was caused mainly by segments without CR but preserved perfusion, fatty acid or glucose utilization. The substantial number of segments with preserved glucose and fatty acid utilization but without contractile reserve, suggests an underestimation of myocardial viability by dobutamine echocardiography.

How morphometric analysis of metastatic load predicts the (un)usefulness of PET scanning: the case of lymph node staging in melanoma.

BACKGROUND: In primary cutaneous melanoma, the sentinel node (SN) biopsy is an accurate method for the staging of the lymph nodes. Positron emission tomography (PET) has been suggested as a useful alternative. However, the sensitivity of PET may be too low to detect SN metastases, which are often small. AIM: To predict the value of PET for initial lymph node staging in melanoma based on morphometric analysis of SN metastatic load, without exposing patients to PET. MATERIALS AND METHODS: In 59 SN positive patients with melanoma, the sizes of tumour deposits in the SNs and subsequent dissection specimens were measured by morphometry and correlated with the detection limits of current and future PET scanners. RESULTS: The median tumour volume within the basin was 0.15 mm(3) (range, 0.0001-118.86). Seventy per cent of these deposits were smaller than 1 mm(3). State of the art PET scanners that have a resolution of about 5 mm would detect only 15-49% of positive basins. Logistic regression analysis revealed no pretest indicators identifying patients expected to have a positive PET. However, the SN tumour load was a significant and single predictor of the presence of PET detectable residual tumour. CONCLUSION: Morphometric analysis of metastatic load predicts that PET scanning is unable to detect most metastatic deposits in sentinel lymph nodes of patients with melanoma because the metastases are often small. Therefore, the SN biopsy remains the preferred method for initial regional staging.

Rapid evaluation of FDG imaging alternatives using head-to-head comparisons of full ring and gamma camera based PET scanners--a systematic review.

AIM: While FDG full ring PET (FRPET) has been gradually accepted in oncology, the role of the cheaper gamma camera based alternatives (GCPET) is less clear. Since technology is evolving rapidly, "tracker trials" would be most helpful to provide a first approximation of the relative merits of these alternatives. As difference in scanner sensitivity is the key variable, head-to-head comparison with FRPET is an attractive study design. This systematic review summarises such studies. METHODS: Nine studies were identified until July 1, 2000. Two observers assessed the methodological quality (Cochrane criteria), and extracted data. RESULTS: The studies comprised a variety of tumours and indications. The reported GC- and FRPET agreement for detection of malignant lesions ranged from 55 to 100%, but with methodological limitations (blinding, standardisation, limited patient spectrum). Mean lesion diameter was 2.9 cm (SD 1.8), with only about 20% < 1.5 cm. The 3 studies with the highest quality reported concordances of 74-79%, for the studied lesion spectrum. Contrast at GCPET was lower than that of FRPET, contrast and detection agreement were positively related. Logistic regression analysis suggested that pre-test indicators might be used to predict FRPET-GCPET concordance. CONCLUSION: In spite of methodological limitations, "first generation" GCPET devices detected sufficient FRPET positive lesions to allow prospective evaluation in clinical situations where the impact of FRPET is not confined to detection of small lesions (< 1.5 cm). The efficiency of head-to-head comparative studies would benefit from application in a clinically relevant patient spectrum, with proper blinding and standardisation of acquisition procedures.

Time course of functional recovery of stunned and hibernating segments after surgical revascularization.

BACKGROUND: Recovery of function is possible in patients with ischemic cardiomyopathy when left ventricular dysfunction is caused by stunning or hibernation. It is plausible that recovery of function after revascularization may take a longer time in hibernating myocardium compared with stunned myocardium. Accordingly, the time courses of functional recovery in hibernating and stunned myocardium were compared. METHODS AND RESULTS: Patients (n=26) with ischemic cardiomyopathy undergoing surgical revascularization were studied; regional perfusion (resting (201)Tl single-photon emission CT), glucose utilization ((18)F-2-deoxyglucose single-photon emission CT), and contractile function (2D echocardiography) were assessed before revascularization. Dysfunctional segments with normal perfusion/glucose utilization were considered to be stunned, and dysfunctional segments with reduced perfusion/preserved glucose utilization were considered to be hibernating. Contractile function was reevaluated 3 months (early) and 14 months (late) after revascularization. Of the 266 dysfunctional segments, 57 (22%) were stunned, 62 (23%) were hibernating, and 147 (55%) were scar tissue. In stunned myocardium, contractile function improved significantly at 3 months, without further improvement at 14 months; 61% of the stunned segments improved at 3 months, and 9% improved at 14 months. In hibernating myocardium, contractile function improved at 3 months, with a further improvement at 14 months; 31% of the hibernating segments improved at 3 months, and 61% showed (additional) recovery at 14 months. CONCLUSIONS: Stunned myocardium is likely to demonstrate early recovery of function, whereas hibernating myocardium may take a longer time to (fully) recover in function after revascularization.

Experimental and clinical evaluation of iterative reconstruction (OSEM) in dynamic PET: quantitative characteristics and effects on kinetic modeling.

UNLABELLED: The purpose of this study was to investigate the quantitative properties and effects of ordered-subset expectation maximization (OSEM) on kinetic modeling compared with filtered backprojection (FBP) in dynamic PET studies. Both phantom and patient studies were performed. METHODS: For phantom studies dynamic two-dimensional emission scans with 10-min frames and 20-min scan intervals were acquired over a 14-h period using an HR+ PET scanner. Various phantoms were scanned: 2-, 5-, 10-, and 20-cm-diameter phantoms filled with an 18F solution (300 kBq/mL) and a NEMA phantom filled with an 18F background (40 kBq/mL) and a cold or 11C insert (450 kBq/mL). Transmission (Tx) scans of 5-60 min were acquired. Data were reconstructed using FBP Hanning 0.5 and OSEM with 2-12 iterations and 12 or 24 subsets. Quantitative accuracy and noise characteristics were assessed. For patient studies, five cardiac, three oncologic, and three brain dynamic 18F-FDG scans were used. Five reconstructions were performed: FBP Hanning 0.5, and OSEM 2 x 12 and OSEM 4 x 16 with and without 5-mm full width at half maximum smoothing. Time-activity curves were calculated using volumes of interest. The input function was derived from arterial sampling. Metabolic rate of glucose (MRglu) was calculated with a standard two-tissue compartment model and Patlak analysis. RESULTS: Contribution of Tx noise to the reconstructed image was smaller for OSEM than for FBP. Differences in signal-to-noise ratio between FBP and OSEM depended on number of iterations and phantom size. Bias with OSEM was observed for regions enclosed within a 5- to 10-fold hotter background. For cardiac studies OSEM 2 x 12 and OSEM 4 x 16 resulted in 13% and 21% higher pixel values and 9% and 15% higher MRglu values compared with FBP. Smoothing decreased all these values to 2%. Similar results were found for most tumor studies. For brain studies MRglu of FBP and OSEM 4 x 16 agreed within 2%. Use of OSEM image-derived input functions for cardiac PET studies resulted in a decrease in calculated MRglu of about 15%. CONCLUSION: For most PET studies OSEM has equal quantitative accuracy as FBP. The higher pixel and MRglu values are explained by the better resolution of OSEM. However, OSEM does not provide accurate image-derived input functions for FDG cardiac PET studies because of bias in regions located within a hotter background.

Relationship between preoperative viability and postoperative improvement in LVEF and heart failure symptoms.

UNLABELLED: The presence of myocardial viability is predictive of improvement in regional left ventricular (LV) function after revascularization. Studies on predicting improvement in global LV function are scarce, and the amount of viable myocardium needed for improvement in LV ejection fraction (LVEF) after revascularization is unknown. Moreover, whether the presence of viability is associated with relief of heart failure symptoms after revascularization is uncertain. Hence, the aims were to define the extent of viable myocardium needed for improvement in LVEF and to determine whether preoperative viability testing can predict improvement in heart failure symptoms. METHODS: Patients (n = 47) with ischemic cardiomyopathy (mean LVEF +/- SD, 30% +/- 6%) undergoing surgical revascularization were studied with 18F-FDG SPECT to assess viability. Regional and global function were measured before and 3-6 mo after revascularization. Heart failure symptoms were graded according to the New York Heart Association (NYHA) criteria, before and 3-6 mo after revascularization. RESULTS: The number of viable segments per patient was directly related to the improvement in LVEF after revascularization (r = 0.79, P < 0.01). Receiver operating characteristic curve analysis revealed that the cutoff level of four viable segments (representing 31% of the left ventricle) yielded the highest sensitivity and specificity (86% and 92%, respectively) for predicting improvement in LVEF. Furthermore, the presence of four or more viable segments predicted improvement in heart failure symptoms after revascularization, with positive and negative predictive values of 76% and 71%, respectively. CONCLUSION: The presence of substantial viability (four or more viable segments, 31% of the left ventricle) on FDG SPECT is predictive of improvement in LVEF and heart failure symptoms postoperatively.

Characteristics of a new fully programmable blood sampling device for monitoring blood radioactivity during PET.

The first performance tests of a new fully programmable blood sampling device for monitoring blood radioactivity during positron emission tomography (PET) are described. Blood is withdrawn through 1-mm internal diameter tubing using an infusion pump which can be operated at rates varying from 0 to 600 ml/h. Activity in blood is measured by a 6-cm-thick bismuth germanate crystal connected to a photomultiplier tube and multichannel analyser (MCA) which are positioned within 6 cm lead shielding. Positioning of the tubing is an exact and simple procedure. The minimal readout time of the MCA is 1 s. Two independent energy windows can be set. Operation of the pump and MCA is fully controlled by a PC, i.e. sampling time, interval time and pump rate can be varied at any time during the PET scan by user-defined scripts. A number of characteristics of the new system were studied, such as sensitivity, dead time, linearity, effect of background radiation and pump rate as a function of input pressure. In addition, dispersion was measured as a function of pump rate. Finally, first clinical results were compared with manual samples. The sensitivity equalled 0.7 and 0.2 cps/Bq for 511- and 1022-keV 30% energy windows, respectively, and the system dead time was 500 ns. The system remained linear within 2% with activity concentrations up to 2.5 MBq/cc. Short-term reproducibility was better than 3% for a 1-h period. Long-term reproducibility was about 5% (ISD), which was mainly caused by variation in the diameter of the tubing. If the device was positioned in such a way that maximum shielding was directed towards the patient, the effects of background radiation from the patient on the measured activity concentration for clinically relevant conditions was minimal (<3%). Pump rate varied with input pressure, but remained constant for a given pressure. Dispersion constants smaller than 0.14 s(-1) were observed for pump rates higher than 300 ml/h, indicating that the system dispersion is small. Clinical data showed an excellent agreement to within 3% (ISD) between the results obtained with the new system and manual samples. With the continuous blood sampler radioactivity in blood can be measured accurately during the entire course of the PET scan. Furthermore, the system is fully programmable allowing adjustment of all parameters during a single PET scan.

Evaluation of strength of healing fractures with dual energy Xray absorptiometry.

Dual energy xray absorptiometry was investigated as a method for evaluation of the strength of closed tibial fractures. In 40 goats, a closed midshaft fracture was created in the left tibia. The fractures were stabilized with an external fixator. After 2 weeks (n = 21) and after 4 weeks (n = 19), both tibias were explanted and, using dual energy xray absorptiometry, bone mineral density and bone mineral content were measured in a 1 cm region. With nondestructive bending tests, area ratio and stiffness index were determined and torsional strength and torsional stiffness were determined with a torsional test to failure. Linear regression analysis was used to calculate the squared correlation coefficients for the relations between dual energy xray absorptiometry and the outcome of the mechanical tests. The squared correlation coefficients for the relation between bone mineral density and torsional strength, torsional stiffness, and area ratio and stiffness index were 0.72, 0.76, 0.64, and 0.72, respectively. The squared correlation coefficients for the relation between bone mineral content and these mechanical parameters were 0.72, 0.77, 0.63, and 0.77, respectively. The results using dual energy xray absorptiometry indicate the strength of healing closed fractures. Additional research is required to investigate specific aspects of this technique.

Resorbable calcium phosphate particles as a carrier material for bone marrow in an ovine segmental defect.

Resorbable calcium phosphate ceramics are only osteoconductive; therefore, their combination with osteogenic substances may lead to stimulation of bone healing. In the present study this combination, using autologous bone marrow, was investigated. In 31 sheep, a 3-cm tibial segmental defect was created and stabilized with an intramedullary nail. The animals were divided into four groups: empty defects (group 1, n = 7), and defects filled with 10-mL dense resorbable calcium phosphate particles (group 2, n = 8), with 10-mL particles soaked in bone marrow (group 3, n = 8), or with 10-mL autologous bone (group 4, n = 8). On evaluation after 12 weeks, significantly higher values were seen in group 3 than in group 2 for callus volume (p = .016), bone mineral density ratio (p = .03), bone mineral content ratio (p = .04), torsional strength (p = .005), and torsional stiffness (p = .01). For all end points, the outcome of group 3 was lower than that of group 4. In the histology, there was direct contact between newly formed bone and remnants of the particles. There were no signs of inflammatory reactions. Although a stimulatory effect of bone marrow was seen, the combination of resorbable calcium phosphate particles with bone marrow does not provide an alternative for autologous bone grafting.

Normal osteoconduction and repair in and around submerged highly bisphosphonate-complexed hydroxyapatite implants in rat tibiae.

BACKGROUND: Ceramic hydroxyapatite implants have been used in dentistry for their unique compatibility with alveolar bone. Recently it was reported that bisphosphonates may be beneficial in preventing alveolar bone destruction associated with natural and experimental periodontal disease. Furthermore, bisphosphonate does prevent resorption of alveolar bone following mucoperiosteal flap surgery. We undertook a preliminary study evaluating the effects of highly bisphosphonate-complexed hydroxyapatite implants on osteoconduction and repair in rat tibiae. METHODS: Porous hydroxyapatite implants were pre-incubated in 10(-2)M bisphosphonate solutions at pH 3.49 and pH 7.32. The implants had a diameter of 2.1 mm and a height of 2 mm and adsorbed 115 microg bisphosphonate in vitro. Bisphosphonate/hydroxyapatite implants and plain hydroxyapatite implants were inserted in opposite tibial metaphyses of 35 rats. The measurement errors for the mineral density (MD) of the implants and the proximal trabecular mineral bone density (TD) were estimated by peripheral computed tomography and the bone mineral density (BMD) measurement error by dual x-ray absorptiometry. RESULTS: The measurement errors for the MD of the implants and the TD by peripheral computed tomography were 0.81% and 1.96%, respectively ex vivo. The BMD measurement error estimated by dual x-ray absorptiometry was 0.51% ex vivo. TD and BMD for bisphosphonate/hydroxyapatite implants were insignificantly higher compared to plain hydroxyapatite implants. Bisphosphonate/hydroxyapatite pre-incubated at pH 7.32 were found to be nondegradable implants, while bisphosphonate/hydroxyapatite (pH 3.49) implants were slowly degradable and lost a significant 5% of their density. Histologically, all bisphosphonate/hydroxyapatite implants appeared to be fully integrated and effective as bone replacement material in rat tibial bone. They exhibited vascularization and osteoconduction of tibial bone growth along and inside their porous structure. CONCLUSIONS: Our study suggests that normal osteoconduction and repair occurred in and around the highly bisphosphonate-complexed hydroxyapatite implants in rat tibiae.

Alveolar bone response to submerged bisphosphonate-complexed hydroxyapatite implants.

BACKGROUND: In most studies using submerged hydroxyapatite implants, maintenance of alveolar bone after tooth extraction was attempted with plain hydroxyapatite materials. However, clinical results have shown that hydroxyapatite may require biological modification with a bone resorption-inhibiting agent which may be beneficial for maintenance of alveolar bone. We conducted experimental and clinical studies to evaluate the effect of highly bisphosphonate-complexed hydroxyapatite implants on osteoconduction and repair in alveolar bone. METHODS: Porous hydroxyapatite implants were pre-incubated in 10(-2)M bisphosphonate solutions at pH 3.49. The implants had a diameter of 2.1 mm and a height of 2 mm and adsorbed 115 microg bisphosphonate. Five goats were implanted with 4 plain hydroxyapatite implants on each side of the mandible in root extraction sockets for the precision analysis of dual x-ray absorptiometry (DEXA) measurements. Ten goats were implanted with 4 bisphosphonate/hydroxyapatite implants on one side of the mandible and 4 plain hydroxyapatite implants on the opposite mandible. In a clinical study, 23 bisphosphonate/hydroxyapatite implants were placed in periodontally destroyed tooth root sockets and followed up during one year. RESULTS: The range for the bone mineral density (BMD) measurement errors for goat histologic sections was 0.48% to 1.03%. There were large differences in peri-implant BMDs in the left and right mandible of the same goat, irrespective as to whether hydroxyapatite or bisphosphonate/hydroxyapatite implants were present. This was due to local anatomical differences typical of alveolar bone. These differences were not significant. Histologically, all bisphosphonate/hydroxyapatite as well as hydroxyapatite controls appeared to be fully integrated and effective as bone replacement material in goat alveolar bone. They exhibited vascularization and osteoconduction of alveolar bone growth along and inside their porous structure. In patients peri-implant healing was clinically and radiographically comparable to plain hydroxyapatite implants. All implants were retained and no dehiscences developed. Radiographically, peri-implant radiolucencies disappeared and alveolar bone was deposited in close proximity to the implants. CONCLUSIONS: This study contributes to the understanding of the biological properties of hydroxyapatite implants as carriers for the bone-modulating agent bisphosphonate. Our study suggests that normal osteoconduction and repair occurred in alveolar bone around the highly bisphosphonate-complexed hydroxyapatite implants.

Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: A phase I therapy study was conducted to determine the safety, maximum tolerated dose (MTD), pharmacokinetics, dosimetry, immunogenicity, and therapeutic potential of 186Re-labeled anti-CD44v6 chimeric monoclonal antibody (cMAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC). The potential of a diagnostic study with 99mTc-cMAb U36 to predict the biodistribution of 186Re-cMAb U36 was evaluated. METHODS: Thirteen patients with recurrent or metastatic HNSCC were given 750 MBq 99mTc-cMAb U36 (2 mg) followed 1 wk later by a single dose of 186Re-cMAb U36 (12 or 52 mg) in radiation dose-escalating steps of 0.4, 1.0, and 1.5 GBq/m2. After each administration, planar and SPECT images were obtained, and the pharmacokinetics and development of human antimurine as well as anti-cMAb responses were determined. Radiation absorbed doses to tumor, red marrow, and organs were calculated. RESULTS: Administration was well tolerated, and excellent targeting of tumor lesions was seen in all patients. Dose-limiting myelotoxicity (thrombocytopenia being most prominent) was the only toxicity observed, resulting in grade 4 myelotoxicity in 2 patients treated with 1.5 GBq/m2. The MTD was established at 1.0 GBq/m2, at which a transient grade 3 thrombocytopenia was seen in 1 patient. One patient showed stable disease for 6 mo after treatment at the MTD. The 2 patients with dose-limiting myelotoxicity showed a marked reduction in tumor size. The reduction was of short duration and, therefore, not considered an objective response. Tumor absorbed doses at MTD ranged from 3.0 to 18.1 Gy. Red marrow doses ranged from 20 to 112 cGy (mean, 51 +/- 16 cGy/GBq) and correlated with platelet nadir (r = 0.8; P < 0.01). Pharmacokinetics varied between patients treated at the same dose level and were accurately predicted by the diagnostic procedure. Five patients experienced a human anti-cMAb response, 1 of which was a human antimouse antibody response. CONCLUSION: This study shows that 186Re-cMAb U36 can be safely administered, with dose-limiting myelotoxicity at 41 mCi/m2. The use of cMAb U36 instead of its murine counterpart did not decrease the induction of human antibody responses. The availability of a 99mTc-labeled diagnostic study that can predict the pharmacokinetics of 186Re-cMAb U36 offers the possibility of using such a study for selection of a safe radioimmunotherapy dose.