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PubMed2006

[Experimental study of the anti-tumor effect of arsenic trioxide or thalidomide alone and combination of both for treatment of myelodysplastic syndrome model].

OBJECTIVE: To investigate the anti-tumor effect and the possible mechanism of arsenic trioxide (ATO) alone or in combination with thalidomide (THAL) for treatment of SCID mice model transplanted with human myelodysplastic syndrome (MDS) cell line MUTZ-1 cells. METHODS: (1) The animal model was established in SCID mice; 75 SCID mice and 10 BALB/CA-nude mice were studied in this experiment. MUTZ-1 cells were cultured in vitro and made for mono-cell suspension (with 1 x 10(8)/ml cell density and in exponential growth behavior) and were subcutaneously implanted into 4-6-week-old first-generation SCID mice and BALB/CA-nude mice. The biological characteristics of the subcutaneous tumor cells were evaluated by the methods of cell morphology, histopathology, immunology by flow cytometer, chromosome analysis and immunohistochemistry (IHC). Subsequently, the tumor cells from first-generation mice model were respectively subcutaneously implanted into 61 second-generation SCID mice and 8 BALB/CA-nude mice and the rate of the tumor formation and the latent period of the tumor formation were observed. (2) In vivo, 56 MDS-SCID mice were randomly grouped; 40 of them were used as ATO treated groups [5.0 microg or 7.5 microg/(g.d) intraperitoneal injection (i p) 5 d a week, x 3 weeks] alone or in combination with THAL 8 microg/(g.d), x 3 week or THAL alone and 16 mice as the control groups [with 0.9% NaCl 10 microl/(g.d) i p or untreated]. The mean tumor diameters (MTD) of subcutaneous tumors were measured with slide gauge and the therapeutic effects and the survival period and the rates of survival were evaluated by the methods of histopathology, IHC, microvessel density count (MVD), DNA ladder, TUNEL and PI with flow cytometry. RESULTS: (1) The rate of the subcutaneous tumor formation was higher (98.4%, 60/61) in SCID mice than in BALB/CA-nude mice (62.5%, 5/8) (P = 0.0027). The latent period of the tumor formation was significantly longer (23 - 28 d, median 26 d) in BALB/CA-nude mice than that in SCID mice (10 - 17 d, median 12 d) (Z = 4.605, P < 0.001). The biological characteristics of the tumor cells in the MDS-SCID mice model were evaluated and considered as of anthropo-source and were consistent with that of MUTZ-1 cells, which showed that the MDS-SCID mice model was successfully established. (2) In vivo, the marked inhibitory effect on the subcutaneous tumors growth (F = 146.94, P = 0.000) and the higher rates of cells apoptosis were seen in the groups treated with ATO 5.0 microg or 7.5 microg alone or in combination with THAL than in control groups (F = 30.10, P = 0.000). The longer-survival periods (F = 25.11, P < 0.01) with lower toxicity were only observed in lower-dose group of ATO 5.0 microg than in other treated groups and control groups. THAL alone group had a mild inhibitory effect on the tumors growth (> 2 weeks) with a longer-survival period and higher-rate of survival than controls, but had no events of cell apoptosis. The expression of vascular endothelial growth factor (VEGF) protein and CD34 protein and MVD were markedly down-regulated by THAL compared with control groups (P < 0.01), suggesting that the possible mechanisms of the inhibitory effect on tumor growth by THAL related to inhibition of vascular endothelial growth. The legs paralysis in 2 MDS-SCID mice was observed after treatment with THAL alone (11 d and 15 d, respectively), which were considered as the side-effect of THAL associated with deep venous thrombotic (DVT) events and the mechanism for these events is unclear. The therapeutic effects were unsatisfied in the group treated with ATO 7.5 microg in combination with THAL due to more intense toxicity and the shorter-survival periods than other treated groups (P < 0.001). CONCLUSIONS: (1) The Hum-MDS-SCID mice model was successfully established, which served as an animal model for studying pathogenesis of MDS and therapeutic agents selection. (2) ATO had marked inhibitory effect on the subcutaneous tumors growth in MDS-SCID mice model in vivo. The longer-survival periods and higher-rates of survival with lower toxicity were observed in lower-dose ATO (5.0 microg) alone than other groups. The mechanisms of the anti-tumor effect of ATO were considered to be related to inducing cells apoptosis, but in the case of THAL, related to inhibition of vascular endothelial growth. (3) The results do not support the preconceived hypothesis of a synergistic effect of ATO (7.5 microg) in combination with THAL for treatment of MDS mice model due to the more intense toxicity and the shorter-survival periods in the treated group. Whether or not this will translate into clinically relevant effect of the ATO or THAL in MDS patients deserves further investigation.

Animals↗

PubMed1997

Crystal structure of a 30 kDa C-terminal fragment from the gamma chain of human fibrinogen.

BACKGROUND: Blood coagulation occurs by a cascade of zymogen activation resulting from minor proteolysis. The final stage of coagulation involves thrombin generation and limited proteolysis of fibrinogen to give spontaneously polymerizing fibrin. The resulting fibrin network is covalently crosslinked by factor XIIIa to yield a stable blood clot. Fibrinogen is a 340 kDa glycoprotein composed of six polypeptide chains, (alphabetagamma)2, held together by 29 disulfide bonds. The globular C terminus of the gamma chain contains a fibrin-polymerization surface, the principal factor XIIIa crosslinking site, the platelet receptor recognition site, and a calcium-binding site. Structural information on this domain should thus prove helpful in understanding clot formation. RESULTS: The X-ray crystallographic structure of the 30 kDa globular C terminus of the gamma chain of human fibrinogen has been determined in one crystal form using multiple isomorphous replacement methods. The refined coordinates were used to solve the structure in two more crystal forms by molecular replacement; the crystal structures have been refined against diffraction data to either 2.5 A or 2.1 A resolution. Three domains were identified in the structure, including a C-terminal fibrin-polymerization domain (P), which contains a single calcium-binding site and a deep binding pocket that provides the polymerization surface. The overall structure has a pronounced dipole moment, and the C-terminal residues appear highly flexible. CONCLUSIONS: The polymerization domain in the gamma chain is the most variable among a family of fibrinogen-related proteins and contains many acidic residues. These residues contribute to the molecular dipole moment in the structure, which may allow electrostatic steering to guide the alignment of fibrin monomers during the polymerization process. The flexibility of the C-terminal residues, which contain one of the factor XIIIa crosslinking sites and the platelet receptor recognition site, may be important in the function of this domain.

Amino Acid Sequence↗

PubMed2001

Effect of topical alendronate on root resorption of dried replanted dog teeth.

Alendronate (ALN) is a third generation bisphosphonate with demonstrated osteoclast inhibitory activity that may slow down the resorptive process after severe traumatic injuries. Eighty-two premolar roots of five mongrel dogs were endodontically treated and restored, extracted and treated as follows: 70 roots were bench dried for either 40 or 60 min. Thirty-eight of these roots were then soaked for 5 min in a 1 mM solution of ALN in Hanks' Balanced Salt Solution (HBSS) and replanted. Thirty-two roots were soaked for 5 min in HBSS and replanted. In the remaining 12 roots which were not exposed to the bench drying procedure, a 0.5 mM deep lingual mid-root cemental defect was made. Six of these roots were soaked in a 1 mM solution of ALN in HBSS for 5 min and replanted. The other six roots were soaked for 5 min in HBSS and replanted. Historical negative and positive controls were used from similarly treated teeth in our previous studies. After 4 months the dogs were killed and the roots prepared for histological evaluation. Five-microm-thick cross-sections of the root and surrounding tissue taken every 70 microm were evaluated for healing according to the criteria of Andreasen. In the 12 roots with cemental defects, healing with cementum of the damaged root surface was evaluated. In addition, residual root mass was also measured to determine the extent of root structure loss for each soaking method. Cemental healing took place in all 12 artificially damaged roots, indicating that these soaking media did not inhibit cementogenesis. The alendronate-soaked roots had statistically significantly more healing than the roots soaked in HBSS without alendronate. This improvement in healing was seen in all dogs except one and in all teeth except the first premolar. Soaking in alendronate also resulted in significantly less loss in root mass due to resorption compared to those teeth soaked in HBSS without alendronate.

Administration, Topical↗

PubMed2004

Radiation dosimetry of a conformal heat-brachytherapy applicator.

The purpose of this paper is to report the radiation dosimetric characteristics of a new combination applicator for delivering heat and radiation simultaneously to large area superficial disease <1.5 cm deep. The applicator combines an array of brachytherapy catheters (for radiation delivery) with a conformal printed circuit board microwave antenna array (for heat generation), and a body-conforming 5-10 mm thick temperature-controlled water bolus. The rationale for applying both modalities simultaneously includes the potential for significantly higher response rate due to enhanced synergism of modalities, and lower peak toxicity due to temporal extension of heat and radiation induced toxicities. Treatment plans and radiation dosimetry are calculated with IPSA (an optimization tool developed at UCSF) for 15 x 15 cm(2) and 35 x 24 cm(2) applicators, lesion thicknesses of 5 to 15 mm, flat and curved surfaces, and catheter separation of 5 and 10 mm. The effect on skin dose of bolus thickness and presence of thin copper antenna structures between radiation source and tissue are also evaluated. Results demonstrate the ability of the applicator to provide conformal radiation dose coverage for up to 15 mm deep target volumes under the applicator. For clinically acceptable plans, tumor coverage is > 98%, homogeneity index > 0.95 and the percentage of normal tissue irradiated is < 20%. The dose gradient at the skin surface varies from 3 to 5 cGy/mm depending on bolus thickness and lesion depth. Attenuation of the photon beam by the printed circuit antenna array is of the order 0.25% and secondary electron emissions are absorbed completely within 5 mm of water bolus and plastic layers. Both phenomena can then be neglected in dose calculations allowing commercial software to be used for treatment planning. This novel applicator should prove useful for the treatment of diffuse chestwall disease located over contoured anatomy that may be difficult to treat with single field external beam therapy. By delivering heat and radiation simultaneously, increased synergism is expected with a TER in the range of 2-5. Lowering radiation dose by an equivalent factor may produce lower radiation toxicity with similar efficacy, while preserving the option of subsequent retreatment(s) with thermoradiotherapy in order to further extend patient survival.

Algorithms↗

PubMed1998

14N electron spin-echo envelope modulation of the S = 3/2 spin system of the Azotobacter vinelandii nitrogenase iron-molybdenum cofactor.

Wild-type nitrogenase MoFe protein shows a deep 14N electron spin-echo envelope modulation (ESEEM) arising from a nitrogen nucleus (N1) coupled to the S = 3/2 spin system of the FeMo-cofactor of the MoFe protein. A previous ESEEM study on altered MoFe proteins generated by substitutions at the alpha-195-histidine position suggested that alpha-195-histidine provides a hydrogen bond to the FeMo-cofactor but is not the source of the 14N1 modulation [DeRose et al. (1995) Biochemistry 34, 2809-2814]. This study also raised the possibility of a correlation between ESEEM spectroscopic properties and the nitrogenase phenotype. We now report ESEEM studies on altered MoFe proteins with substitutions at residues alpha-96-arginine, alpha-359-arginine, and alpha-381-phenylalanine to (i) assign the first-shell hydrogen bonding as revealed by the 14N modulation; (ii) explore the mechanistic relevance of the ESEEM signatures to nitrogenase activity; and (iii) study microscopic changes within the polypeptide environment of the FeMo-cofactor. Present ESEEM data reveals that two kinds of 14N modulations are present in wild-type MoFe protein. A new 2-dimensional procedure for high-precision analysis of the ESEEM data of the MoFe proteins shows that the deep wild-type ESEEM modulation (denoted N1) has a hyperfine-coupling constant of Aiso = 1.05 MHz and nuclear quadrupole coupling parameters of e2qQ = 2.17 MHz, eta = 0.59; the other (denoted N2) has a smaller hyperfine coupling of Aiso = approximately 0.5 MHz and e2qQ = approximately 3.5 MHz, eta = approximately 0.4. The N2 ESEEM pattern is more obvious when unmasked by substitutions that result in the loss of the deep N1 modulation. Correlations of the ESEEM properties and catalytic activities of the altered MoFe proteins suggest that (i) the side chain of the alpha-359-arginine is the source of the deep ESEEM N1 modulation; (ii) one or both of the amide nitrogens of alpha-356-glycine/alpha-357-glycine are responsible for the weak N2 modulation; (iii) substitution of the nonpolar alpha-381-phenylalanine residue, as well as substitution of either the alpha-195-histidine or alpha-359-arginine residues, can eliminate the N1 interaction with FeMo-cofactor; and (iv) ESEEM can be used to detect slight reorientations of FeMo-cofactor within its polypeptide pocket, although the mechanistic relevance of the loss or perturbation of the hydrogen-bonding interactions between FeMo-cofactor and polypeptide environment has not yet been established.

Azotobacter vinelandii↗

PubMed2002

Out of hospital antithrombotic prophylaxis after total hip replacement: low-molecular-weight heparin, warfarin, aspirin or nothing? A cost-effectiveness analysis.

Several studies have suggested that after hip replacement the risk of deep vein thrombosis and subsequent pulmonary embolism (PE) may persist for some weeks. Antithrombotic prophylaxis, however, is generally stopped at hospital discharge. Using a Markov-based decision analysis, we measured the clinical and economical consequences of extending prophylaxis after hospital discharge up to 4 weeks and 6 weeks, using either low-molecular-weight heparin (LMWH), warfarin, or aspirin. In the reference strategy, antithrombotic prophylaxis was stopped at hospital discharge. Outcome measures included the number of PE prevented, major haemorrhages induced, overall costs in Euro (EUR) and specific costs generated by each PE prevented for all strategies. Extending prophylaxis up to 4 weeks after discharge was safe and cost saving for all prophylactic regimens, although LMWH was the most effective strategy. Our results were most sensitive to the rate of haemorrhages, the efficacy of treatment and its costs. Specifically, the number of PEs prevented exceeded that of haemorrhages induced if the efficacy of antithrombotic prophylaxis was > or = 40% (assuming a low rate of haemorrhages of 0.1% per week), and > or = 70% (assuming a high rate of haemorrhages of 0.25% per week). LMWH and warfarin remained cost saving unless their costs were more than doubled compared to that of baseline value. Although less effective than LMWH and warfarin, prophylaxis with aspirin was cost saving in all scenarios tested. Extending prophylaxis up to 6 weeks was also effective (the number of PEs prevented overwhelmed that of major haemorrhages induced), but only for the scenario of a low bleeding risk (0.1%/week). In this strategy, aspirin remained cost saving, while the costs for each PE prevented became high (EUR 10,000 to EUR 20,000) if the costs of LMWH and warfarin increased. After hip replacement, extending antithrombotic prophylaxis up to 4 weeks after hospital discharge is effective and cost saving. Although LMWH is the most effective strategy, warfarin, and to a lesser extent aspirin may be alternate options if ressources are a major concern. Extending prophylaxis up to 6 weeks is more risky in patients at high bleeding risk, and generates additional costs.

Ambulatory Care↗

PubMed2000

An in vitro cell culture system to study the influence of external pneumatic compression on endothelial function.

PURPOSE: External pneumatic compression (EPC) is an effective means of prophylaxis against deep venous thrombosis. However, its mechanism remains poorly understood. Understanding of the biological consequences of EPC is an important goal for optimizing performance of the EPC-generating device and providing guidance for clinical use. We present a new in vitro cell culture system (Venous Flow Simulator) that simulates blood flow and vessel collapse conditions during EPC, and we examine the influence of these factors on endothelial cell (EC) fibrinolytic activity and vasomotor function. METHODS: An in vitro cell culture system was designed to replicate the hemodynamic shear stress and vessel wall strain associated with induced blood flow during different modes of EPC. Human umbilical vein endothelial cells were cultured in the system and subjected to intermittent flow, vessel collapse, or a combination of the two. The biologic response was assessed through changes in EC morphology and the expression of fibrinolytic factors tissue plasminogen activator, plasminogen activator inhibitor type 1, profibrinolytic receptor (annexin II), and vasomotor factors endothelial nitric oxide synthase and endothelin-1. RESULTS: The cells remained attached and viable after being subjected to intermittent pulsatile flow (F) and tube compression (C). In F and F + C, cells aligned in the direction of flow after 6 hours. Northern blot analysis of messenger RNA shows that there is an upregulation of tissue plasminogen activator expression (1.95 +/- 0.19 in F and 2.45 +/- 0.46 in FC) and endothelial nitric oxide synthase expression (2.08 +/- 0.25 in F and 2.11 +/- 0.21 in FC). Plasminogen activator inhibitor type 1, annexin II, and endothelin 1 show no significant change under any experimental conditions. The results also show that pulsatile flow, more than vessel compression, influences EC morphology and function. CONCLUSION: Effects on ECs of intermittent flow and vessel collapse, either individually or simultaneously, were simulated with an in vitro system of new design. Initial results show that intermittent flow associated with EPC upregulates EC fibrinolytic potential and influences factors altering vasomotor tone. The system will facilitate future studies of EC function during EPC.

Blood Flow Velocity↗

PubMed2006

Norepinephrine modulates the inflammatory and proliferative phases of wound healing.

BACKGROUND: Injury results in the massive release of norepinephrine (NE) into the peripheral circulation. Recent investigations have demonstrated functional adrenoreceptors on the cellular mediators of cutaneous wound healing and NE-induced phenotypic alterations in immune cells have been demonstrated in vitro. Despite this, there is little description of how NE might alter the phases of wound healing in vivo. The purpose of this study was to compare cutaneous wound healing in norepinephrine-intact and norepinephrine-depleted mice. METHODS: Norepinephrine-depleted (NED) mice were generated by chemical axotomy with 6-hydroxydopamine and compared with norepinephrine-intact (NEI) animals (n = 6-12 per group, per time point). Using an excisional wound model, neutrophil recruitment was measured by myeloperoxidase assay. Macrophage recruitment and angiogenesis were measured by immunohistochemistry and re-epithelialization was determined histologically. The development of incisional wound disruption strength was determined over time. Finally, macrophage scavenger function was assessed by an in vitro latex bead phagocytosis assay. RESULTS: Wounds from NEI mice demonstrated greater neutrophil infiltration than NED wounds (24, 72 hours; p < 0.05). Wound macrophage recruitment was initially higher in NEI animals (24 hours, p < 0.05), but was eventually surpassed by that of NED animals (120 hours, p < 0.05). Angiogenesis was decreased while re-epithelialization was accelerated in NEI animals (p < 0.05). Wound disruption strength and macrophage scavenger function were unaltered between NED and NEI mice. CONCLUSIONS: Norepinephrine modulates the inflammatory and proliferative phases of wound healing in a temporally defined, cell-specific manner. By increasing recruitment of innate immune cells and expediting wound closure, norepinephrine appears to play a protective role in defense against infection.

Animals↗

PubMed1993

Role of synaptic excitation in the generation of bursting-induced epileptiform potentials in the endopiriform nucleus and piriform cortex.

1. The mechanism of generation of epileptiform excitatory postsynaptic potentials (e-EPSPs) induced by bursting activity in vitro was examined in slices of piriform cortex. 2. Previous study revealed that e-EPSPs in piriform cortex are generated in the subjacent endopiriform nucleus, perhaps with a contribution from the claustrum and deep part of layer III of piriform cortex. A puzzling feature of these e-EPSPs was their abrupt origin at long latency with little sign of preceding abnormal activity. 3. Systematic mapping revealed that within spatially restricted regions of the endopiriform nucleus there is an irregular buildup in extracellularly recorded multiunit activity and intracellularly recorded depolarization that precedes the onset of e-EPSPs. Analysis of latency revealed that these "slow-onset" e-EPSPs precede the more widely distributed "abrupt-onset" e-EPSPs, suggesting that they occur at sites of initiation. 4. The hypothesis was tested that the buildup associated with slow-onset e-EPSPs is dependent on synaptically mediated excitation. According to this hypothesis, all-or-none e-EPSPs originate when mutually excitatory (positive feedback) interactions within a population of cells in the endopiriform nucleus become self-regenerative. 5. Predictions from the regenerative positive feedback hypothesis that were successfully verified include the presence of excitatory synaptic connections between cells in the endopiriform nucleus; the consistent prediction of a subsequent e-EPSP from the occurrence of the accelerating buildup in population activity; the occurrence of inhibitory postsynaptic potentials (IPSPs) together with EPSPs during the buildup period; and the blockage of the buildup and e-EPSP by a low concentration of a specific excitatory amino acid antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). 6. Blockage of e-EPSPs by a concentration of DNQX that was much less than that required to block monosynaptic EPSPs in the endopiriform nucleus indicates that synaptic reverberation is mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) type excitatory amino acid receptors. 7. D-2-amino-5-phosphonovaleric acid (D-APV) reduced the duration and amplitude of e-EPSPs but did not block their occurrence, indicating that N-methyl-D-aspartate (NMDA) receptors have a boosting effect on e-EPSPs but are not required for their generation. This is in contrast to the induction of e-EPSPs by bursting activity for which NMDA receptor activation is required. 8. Outside the region of initiation e-EPSPs propagated through the endopiriform nucleus at a velocity of 0.1 m/s.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Toxic action/toxicity.

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a

Animals↗

PubMed2000

Gamma knife radiosurgery as a primary treatment for prolactinomas.

OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.

Humans↗