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Combination of subareolar blue dye and peritumoral RI for sentinel lymph node biopsy.

BACKGROUND: The identification rate of sentinel lymph nodes (SLNs) is variable because numerous different methods employing different tracers have been used for sentinel lymph node detection. The aim of this study was to determine the optimal technique for sentinel lymph node biopsy (SLNB). METHODS: From May 1999 to December 2001, SLNB was performed for 376 patients with T1-3 and N0-1 primary breast cancer using blue dye alone, radioisotope (RI) alone and combination of RI and blue dye. Two hundred sixty-eight patients underwent SLNB using blue dye alone. They were divided into 4 groups (Group A: n=50; peritumoral injection, Group B: n=83; the first half to receive subareolar injection, Group C: n=83; the second half to receive subareolar injection, and Group D: n=52; small incision according to an axillary skin landmark). One hundred eight patients underwent SLNB using RI. Tin colloid was used in 49 cases (Tin Colloid Group) and phytate in 59 cases (Phytate Group). Among them, 29 patients underwent injection of RI alone and 79 patients received a combination of RI and blue dye. RESULTS: The identification rates of SLN using blue dye alone were 60%, 82%, 92% and 79% in Groups A, B, C and D, respectively. The identification rates of SLN in patients receiving RI alone and in those receiving combination of RI and blue dye were 40% and 89%, respectively, in Tin Colloid Group, and 92% and 94%, respectively, in Phytate Group. CONCLUSION: When using blue dye alone, subareolar injection provided a better identification rate than peritumoral injection. The combination of peritumoral phytate and subareolar blue dye provided the best identification rate (94%) in all the groups. The combination of intraparenchymal phytate and subareolar blue dye was the most efficient technique for sentinel node biopsy in breast cancer patients.

Breast Neoplasms↗

Parenteral water/oil emulsions containing hydrophilic compounds with enhanced in vivo retention: formulation, rheological characterisation and study of in vivo fate using whole body gamma-scintigraphy.

The preparation and characterization of parenteral water-in-oil (w/o) emulsions with a potential for sustained release of hydrophilic drugs was described with emphasis on rheological behaviour and spreading phenomenon after intramuscular (i.m.) injection in rabbit thigh muscle. Both steady state and dynamic rheological parameters were investigated showing Newtonian behaviour at low fraction of disperse phase ratio as opposed to viscoelastic and pseudoplastic behaviour at high fraction of disperse phase. Disappearance and spreading behaviour of hydrophilic radioactive markers, aprotinin (6512 g/mol) and pertechnetate (193 g/mol) entrapped in w/o emulsions from an i.m. injection site was studied by whole body gamma-scintigraphy. The retention of entrapped aprotinin 24 h postinjection was 83 +/- 5% for a low spreading emulsion and 76 +/- 6% for a high spreading emulsion. The corresponding values for pertechnetate were 50 +/- 11 and 23 +/- 2%, respectively. The relatively long retention times were suggested to be related to the good physical stability properties of the present emulsions. It was concluded that the presented w/o emulsions are promising vehicles for sustained release of hydrophilic drugs from an i.m. injection site.

Algorithms↗

The relationships of aerosol deposition, lung size, and the rate of mucociliary clearance.

Although the effect of deposition pattern of an inhaled aerosol upon subsequent mucociliary clearance is well recognized, the influence of lung size on the rate of clearance has not been clearly defined. To examine the relationships of lung size in terms of the forced vital capacity (FVC) and aerosol deposition pattern to the rate of mucociliary clearance, we measured lung retention of an inhaled 8-micron aerosol for 120 min using a gamma camera in 13 healthy nonsmoking volunteers. The deposition pattern of the inhaled aerosol was defined in terms of the initial skew of the distribution of retained activity within the right lung (skew) and the percent retained at 24 hr (R24). Multiple regression analysis showed that FVC was responsible for approximately 36% of the variability in bronchial retention with time, with a lesser contribution from variations in deposition pattern (skew and R24). Mucociliary clearance was significantly slower (i.e., greater bronchial retention) in male subjects than in female subjects which can probably be attributed to the differences in FVC. Variations in lung sizes as well as deposition pattern should therefore be considered when making between subject comparisons of the mucociliary clearance rate.

Adult↗

In vivo evaluation of three different 99mTc-labelled radiopharmaceuticals for sentinel lymph node identification.

This work was designed to compare sentinel lymph node (SLN) uptake of 99mTc-labelled human serum albumin colloid (99mTc-HSAC), 99mTc-labelled antimony sulphur colloid (99mTc-SC) and a 99mTc-labelled dextran 70 solution (99mTc-Dx) and their selectivity in the identification of this node in the right rear footpad (RRF) of normal mice and tumour bearing mice. Radiopharmaceutical uptake in the SLN (popliteal lymph node) and the lumbar lymph node (LLN), the second lymphatic node station from RRF, were measured at different time points post-intradermal or intratumoural injection into the RRF of NIH normal mice and of Balb/c mice harbouring the murine mammary tumour M2. 99mTc-HSAC uptake in the SLN was significantly higher than LLN uptake. The 99mTc-SC demonstrated high uptake in SLN, but accumulation in LLN was also high. 99mTc-Dx showed low uptakes in both SLN and LLN. The intradermal injection resulted in a more effective radiopharmaceutical accumulation in SLN than did the intratumoural inoculation. Data also show that increments in tumour volume reduced radiopharmaceutical uptake in the SLN. Our results show that 99mTc-HSAC exhibits the highest uptake in the SLN combined with the smallest amounts of radiopharmaceutical passing through to the LLN. Therefore, 99mTc-HSAC appears to be the best radiopharmaceutical for sentinel node detection.

Adenocarcinoma↗

Influence of airway and airspace sizes on particle deposition in excised donkey lungs.

Tests of aerosol deposition with breath holding and of lung function were performed on the excised lungs of three donkeys following regional in vivo radioaerosol deposition tests. Corrosion casts were made of the lungs to determine the dimensions of the tracheobronchial (TB) tree, and histological sections were taken to determine average alveolar airspace size. Static lung function tests, i.e., static compliance and specific compliance (Cstat and Cspec), agreed well with the predicted and reported in vivo values, as did the slope of Phase III from the single breath nitrogen washout (SBNW). Dynamic tests, i.e., dynamic compliance (Cdyn) and pulmonary resistance (Rpulm), displayed larger inter- and intra-subject variation, and showed poor agreement with reported in vivo values. Breathholding tests using 0.55 micron diameter aerosol indicated a mean respiratory airspace dimension of 0.16 mm, while the mean alveolar diameter from the lung sections was 0.19 mm. Breathholding tests with 1.18 micron aerosol indicated a mean small airway size of 0.65 mm, corresponding to the sizes of small airways on the corrosion casts. The donkeys have larger central airways but smaller peripheral airways than humans, and greater tracheobronchial deposition efficiency for 5 micron diameter particles. Tracheobronchial deposition in donkeys appears to be concentrated more distally than in humans, and may be related to the monopodal airway branching pattern in the former.

Aerosols↗

Radioguided sentinel node detection in breast cancer patients: comparison of 99mTc phytate and 99mTc rhenium colloid efficacy.

BACKGROUND: Radioguided sentinel node biopsy (SNB) of breast cancer patients has become a standard method for detecting early stage breast cancer. However, no standard radiopharmaceutical exists. METHODS: 99mTc rhenium colloid or 99mTc phytate SNB was used to aid detection in breast cancer patients. For each radiopharmaceutical, 100 patients were examined. The following points were compared: (1) scintigraphic detection rate of axillary sentinel nodes (detectability and number when detectable) and internal mammary sentinel nodes; (2) the number of nodes detected scintigraphically and the number detected during surgery; (3) sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for axillary sentinel nodes. RESULTS: Axillary sentinel nodes of patients were biopsied using either 99mTc rhenium or 99mTc phytate. The number of axillary nodes surgically removed from patients given 99mTc rhenium was 2.28+/-1.08 (mean+/-SD), and the number of axillary nodes surgically removed from patients given 99mTc phytate was 1.68+/-0.82. Some patients given 99mTc rhenium showed a spill-over of radioactivity from sentinel nodes. Concordance of scintigraphically detected nodes and surgical removed nodes was superior for 99mTc phytate compared to that with 99mTc rhenium, with a statistically significant difference. The sensitivity and negative predictive value was superior with 99mTc phytate compared to that with 99mTc rhenium, even though no statistical difference was detectable. However, visualization of internal mammary nodes was superior with 99mTc rhenium. CONCLUSION: In breast cancer patients, 99mTc phytate is a better choice for the detection of axillary SNB than 99mTc rhenium colloid. However, 99mTc rhenium colloid is a better choice for the detection of internal mammary nodes.

Adult↗

Comparative effects of neutral dipolar compounds and lipophilic anions on technetium 99m-hexakis (2-methoxyisobutyl isonitrile) accumulation in cultured chick ventricular myocytes.

RATIONALE AND OBJECTIVES: Non-flow-dependent myocellular accumulation and uptake kinetics of the myocardial perfusion and viability imaging agent, hexakis (2-methoxyisobutyl isonitrile) technetium 99m(I) (Tc-SESTAMIBI), are thermodynamically driven by large negative sarcolemmal and mitochondrial membrane potentials, and can be enhanced by addition of the lipophilic anion, tetraphenylborate (TPB). To further understand the general properties required of a co-administered compound for increasing the kinetic response of Tc-SESTAMIBI to membrane potential, a systematic appraisal of additional candidate lipid-soluble anions and neutral dipolar compounds was undertaken. METHODS: Each compound was biologically tested for its ability to enhance Tc-SESTAMIBI accumulation in a cultured heart cell model, and electronic dipole moments were evaluated using semi-empirical molecular orbital calculations. RESULTS: Of this series, phloretin (100 microM), TPB (10 microM), and to a lesser degree, 8-anilino-1-naphthalene sulfonate (100 microM) enhanced myocellular accumulation of Tc-SESTAMIBI. Phloretin enhancement was pH-dependent, showing maximal effect at pH 7.4, and was not additive to the augmentation induced by TPB. A series of additional lipid soluble anions and structural analogues of phloretin were without effect. CONCLUSION: Although selected compounds enhanced Tc-SESTAMIBI accumulation, overall, no direct relationship of dipole moment to biologic enhancement was demonstrated.

Anilino Naphthalenesulfonates↗

Synthesis of a diaminedithiol bifunctional chelating agent for incorporation of technetium-99m into biomolecules.

The synthesis of a bifunctional chelating agent (BCA), 1, based on the diaminedithiol (DADT) ligand system, is described. The six-step synthetic sequence has been accomplished in 16% overall yield, affording 1, which contains a thiolactone as a reactive moiety, which permits direct coupling to nucleophiles without the formation of byproducts. The reactivity of 1 toward benzylamine and subsequent labeling of the ligand with technetium-99m has been evaluated as a model for preparation of various bioconjugates. Both coupling and exchange labeling occur in high yield under mild conditions, and competition reactions with diethylenetriaminepentaacetic acid (DTPA) indicate the superior stability of the technetium-99m-DADT complex. Preparation of BCA 1 thus provides a new avenue into technetium-labeled radiopharmaceuticals.

Chelating Agents↗

Development of novel mixed-ligand oxotechnetium [SNS/S] complexes as potential 5-HT1A receptor imaging agents.

The "3 + 1" ligand system [SN(R)S/S combination] was applied in order to synthesize neutral mixed-ligand oxotechnetium complexes of the general formula 99mTcO[SN(R)S]/[S] as potential 5-HT1A receptor imaging agents. The complexes are carrying the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, either on the monodentate ligand [S] or on the tridentate ligand [SN(R)S]. The complexes MO[EtN(CH2CH2S)2] [o-MeOC6H4N(CH2CH2)2NCH2CH2S] (3), MO[o- MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2][PhS] (6) and MO[o-MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2] [PhCH2CH2S] (9), where M = 99mTc, were prepared at tracer level using 99mTc glucoheptonate as precursor. For structural characterization, the analogous oxorhenium (M = Re, 1, 4 and 7, respectively) and oxotechnetium (M = 99gTc, 2, 5 and 8, respectively) complexes were prepared by ligand exchange reactions. All products were characterized by elemental analysis and spectroscopic methods. Complexes 1, 4 and 7 were further characterized by crystallographic analysis. For 1, the coordination geometry about rhenium can be described as trigonally distorted square pyramidal (tau = 0.36), while for 4 and 7, as distorted trigonal bipyramidal (tau = 0.66 and tau = 0.61, respectively). The coordination sphere about oxorhenium in all complexes is defined by the SNS donor atom set of the tridentate ligand and the sulfur atom of the monodentate coligand. The structure of the 99mTc complexes 3, 6 and 9 was established by comparative HPLC using authentic oxorhenium and oxotechnetium samples. The binding affinity of oxorhenium compounds for the 5-HT1A receptor subtype was determined in rat brain hippocampal preparations (IC50 = 6-31 nM). Preliminary tissue distribution data in healthy mice revealed the ability of all three 99mTc complexes to cross the intact blood-brain barrier (0.49-1.15% ID at 1 min p.i.). In addition, complexes 6 and 9 showed significant brain retention. These promising results have demonstrated that the SNS/S mixed-ligand system can be used in the development of 99mTc complexes as potential 5-HT1A receptor imaging agents.

Animals↗

Preparation and biological distribution of technetium diphosphonate radiotracers synthesized without stannous ion.

Two HEDP complexes of technetium (either Tc-99 or a mixture of Tc-99 and Tc-99m) have been prepared without the use of stannous ion. The first, Tc(NaBH4)-HEDP, is synthesized by reduction of TcO4- with NaBH4 in the presence of excess HEDP; this is analogous to the preparation of Tc(Sn)-HEDP in commercial kits wherein SN(II) functions as the reductant. The second, Tc-HEDP, is prepared by substitution of HEDP onto the pre-formed, pre-reduced, technetium center TcBr62-. The HEDP-to-Tc ratio in Tc-HEDP was found to be 1.0 by double-labeling procedures (Tc-99 and [3H]HEDP), implying that in solution this material is polymeric or at least dimeric. Preparations of Tc(NaBH4)-HEDP and Tc-HEDP with Tc-99m are excellent bone-imaging agents in both rats and dogs. Tissue distribution studies in rats show that uptake of Tc(NaBH4)-HEDP and Tc-HEDP by the bone is at least equivalent to that achieved by Tc(Sn)-HEDP prepared in commercial kits with Sn(II) as the reductant. Tin is therefore not necessary for the bone-seeking properties of Tc(Sn)-HEDP, and the in vivo distribution of a given HEDP radiotracer seems to depend primarily on the presence of the HEDP ligand and not on the exact nature of the technetium complex itself. Synthesis of technetium radiotracers by a substitution route, rather than by redox, is practicable; this route has the potential of introducing hitherto unattainable flexibility and subtlety into the preparation of technetium radiotracers.

Etidronic Acid↗

Technetium-99m complexes of dimethylaminomethylene diphosphonate (DMAD)--I. Anion exchange HPLC characterization of 99mTc(NaBH4)-DMAD mixtures.

Radiopharmaceutical analogs prepared by sodium borohydride reduction of 99mTcO4- in the presence of DMAD have been characterized by anion exchange HPLC (high performance liquid chromatography) separation of the resulting mixture into component 99mTc-DMAD complexes. The distribution of complexes within a radiopharmaceutical formulation can be manipulated by controlling technetium concentration, pH, presence or absence of air, and time post reaction.

Borohydrides↗