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Biomedical subjects

Y Boucher

Publications and source records attributed to Y Boucher.

At least 37 records · Page 2Linked to original sources
PubMed1999

Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications.

Elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors. The etiology of tumor interstitial hypertension is poorly understood. We have postulated that the solid stress generated by tumor cells growing in a confined space compresses blood vessels and increases tumor microvascular pressure and IFP. To test the hypothesis that neoplastic cell loss would decompress blood vessels and lower IFP, we induced apoptosis in tumors with paclitaxel and docetaxel. Taxanes inhibited the growth of the murine mammary carcinoma (MCa-IV) and of the human soft tissue sarcoma (HSTS-26T). Taxanes induced apoptosis and reduced the density of intact neoplastic cells in both MCa-IV and HSTS-26T. To determine whether neoplastic cell loss decompressed blood vessels, we measured the diameter of tumor vessels in HSTS-26T tumors implanted in transparent dorsal skin fold chambers. At 48 and 96 h after paclitaxel, the diameter of tumor vessels was significantly increased. The increase in vascular diameters was associated with reductions in microvascular pressure and IFP. The changes in neoplastic cell density and IFP were also correlated. In the human glioblastoma U87, which is resistant to paclitaxel, the IFP and cellular density were not modified by paclitaxel treatment. Collectively, these results support the hypothesis that solid stress generated by neoplastic cell proliferation increases vascular resistance and IFP. The increase in vessel diameter induced by paclitaxel and docetaxel suggests that taxanes could improve tumor response by increasing the vascular surface area for delivery of therapeutic agents.

Animals↗
PubMed1999

Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules.

Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulation of tumor MVP enhances transvascular fluid filtration, leading to a 40% increase in total uptake of the specific antibody within 4 hr of its administration. Conversely, neither continuous nor periodic infusion of AII induced any increase in uptake of nonspecific antibodies. Strategies to improve delivery of macromolecules and limitations of this approach are identified.

Animals↗
PubMed1999

Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental validation.

Interstitial fluid movement is intrinsically linked to lymphatic drainage. However, their relationship is poorly understood, and associated pathologies are mostly untreatable. In this work we test the hypothesis that bulk tissue fluid movement can be evaluated in situ and described by a linear biphasic theory which integrates the regulatory function of the lymphatics with the mechanical stresses of the tissue. To accomplish this, we develop a novel experimental and theoretical model using the skin of the mouse tail. We then use the model to demonstrate how interstitial-lymphatic fluid movement depends on a balance between the elasticity, hydraulic conductivity, and lymphatic conductance as well as to demonstrate how chronic swelling (edema) alters the equipoise between tissue fluid balance parameters. Specifically, tissue fluid equilibrium is perturbed with a continuous interstitial infusion of saline into the tip of the tail. The resulting gradients in tissue stress are measured in terms of interstitial fluid pressure using a servo-null system. These measurements are then fit to the theory to provide in vivo estimates of the tissue hydraulic conductivity, elastic modulus, and overall resistance to lymphatic drainage. Additional experiments are performed on edematous tails to show that although chronic swelling causes an increase in the hydraulic conductivity, its greatly increased distensibility (due to matrix remodeling) dampens the driving forces for fluid movement and leads to fluid stagnation. This model is useful for examining potential treatments for edema and lymphatic disorders as well as substances which may alter tissue fluid balance and/or lymphatic drainage.

Animals↗
PubMed1999

Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

Angiostatins↗
PubMed1999

The control of haemorrhage at the operative site during periradicular surgery.

CLINICAL TECHNIQUE: Effective apical sealing in endodontic surgery requires a dry root-end cavity to insert the filling material. A number of procedures for controlling haemorrhage have been described in the literature. An improvement of these techniques is proposed in this paper: by using a mixture of surgical wax and fibres of calcium alginate. This device, easy to place, sterile and non-toxic, permits placement of a root-end filling under more favourable conditions.

Alginates↗
PubMed1998

A photoelastimetric analysis of stress induced by root-end resection.

The aim of this study was to place into perspective some factors that played an important role in the healing of periapical lesions after surgical endodontic procedures. Root-ends were sectioned at different angulations on models and analyzed by photoelastimetry. Results showed that a section of the root-end through a plane perpendicular to the long axis of the tooth offers a better distribution of the stresses exerted on the apical region that the use of an inclined plane. The biological implications of these results have led the authors to propose a plan of resection that is perpendicular to the long axis of the tooth instead of the inclined plane commonly used.

Birefringence↗
PubMed1998

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents.

We have developed a new technique to measure in vivo tumour tissue fluid transport parameters (hydraulic conductivity and compliance) that influence the systemic and intratumoral delivery of therapeutic agents. An infusion needle approximating a point source was constructed to produce a radially symmetrical fluid source in the centre of human tumours in immunodeficient mice. At constant flow, the pressure gradient generated in the tumour by the infusion of fluid (Evans blue-albumin in saline) was measured as a function of the radial position with micropipettes connected to a servo-null system. To evaluate whether the fluid infused was reabsorbed by blood vessels, infusions were also performed after circulatory arrest. In the colon adenocarcinoma LS174T with a spherically symmetrical distribution of Evans blue-albumin, the median hydraulic conductivity in vivo and after circulatory arrest at a flow rate of 0.1 microl min(-1) was, respectively, 1.7x10(-7) and 2.3x10(-7) cm2 mmHg(-1) s. Compliance estimates were 35 microl mmHg(-1) in vivo, and 100 microl mmHg(-1) after circulatory arrest. In the sarcoma HSTS 26T, hydraulic conductivity and compliance were not calculated because of the asymmetric distribution of the fluid infused. The technique will be helpful in identifying strategies to improve the intratumoral and systemic delivery of gene targeting vectors and other therapeutic agents.

Absorption↗
PubMed1998

A teaching model for endodontic surgery.

It is often difficult to achieve realistic simulation in teaching endodontic surgery. There is relatively little material available to students other than animal tissue or human cadavers. We propose a working model for the teaching of this discipline, constructed from casts of a natural skull which reproduce anatomical features such as gingiva, maxillary sinus, or mandibular canal, for example. This model, made of polyurethane resin containing mineral particles, which closely simulates the radiological and tactile differences of the relative densities of spongy bone, cortical bone and teeth, permits close simulation of the conditions under which endodontic surgery may be performed.

Education, Dental↗
PubMed1997

Surgical treatment of a lateroradicular lesion on an invaginated lateral incisor (dens in dente).

The complex anatomy of invaginated teeth makes their endodontic treatment difficult. The case described here reports the successful management of an invaginated tooth presenting with a lateroradicular lesion. After the root was surgically exposed and the radicular defect was cleaned, gutta percha was sealed with a zinc oxide eugenol cement, heat-compacted under 5 degrees, and then cold-burnished. The osseous cavity was filled with Biocorail. Radiographs at 1 month and 5 years show periapical healing with osseous formation. This procedure, resulting in minimal loss of hard tissues, permitted retention of the tooth.

Adult↗
PubMed1997

Interstitial fluid pressure in intracranial tumours in patients and in rodents.

Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 +/- 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.

Adult↗
PubMed1997

Surgical treatment of a periradicular lesion on an invaginated maxillary lateral incisor (dens in dente).

The complex anatomy of invaginated teeth make their root canal treatment difficult. Moreover, this treatment may compromise the future of the tooth if it is destined to support a post-retained coronal restoration. This case reports the successful surgical root canal treatment of an invaginated tooth using a retrograde filling with gutta-percha. After surgical exposure of the root-end and cleaning of the root canal, the gutta-percha was compacted in the root canal which had been coated previously with a zinc oxide-eugenol cement. The gutta-percha was then cold-burnished. Periapical radiographic examination after 1, 2, 3, 6 and 12 months showed periapical healing with osseous formation. This procedure, resulting in minimal loss of hard tissues, permitted subsequent restoration of the tooth.

Adult↗
PubMed1996

Tumor angiogenesis and interstitial hypertension.

Due to the high permeability of tumor vessels to fluids and plasma proteins, the microvascular pressure (MVP) is the principal driving force for interstitial hypertension in solid tumors; as a result, hydrostatic pressures between the microvascular and interstitial space are close to equilibrium. Based on these observations, we hypothesized that the tumor interstitial fluid pressure (IFP) should increase following the onset of angiogenesis. To this end, the relationship between IFP and tumor neovascularization was determined in the human colon adenocarcinoma (LS174T) and the murine carcinoma (MCaIV) implanted in a transparent dorsal skin fold chamber in severe combined immunodeficient mice. Three stages in the development of the tumor neovasculature were characterized by intravital microscopy. Stage I tumors were avascular, stage II was characterized by vascular sprouts and loops, and in stage III, the tumor vasculature was completely developed and blood flow was obvious. The IFP was measured with micropipettes and a servo-null system. For both tumor types, the IFP in stage I tumors was close to 0 mm Hg, and IFP increased significantly from one stage to the next. To further confirm that interstitial hypertension was associated with the development of the tumor vasculature, IFP was measured in LS174T spheroids. The mean pressure in spheroids was 0.2 +/- 0.3 mm Hg. In stage III tumors, the IFP was compared to the MVP. In MCaIV, the MVP was comparable to the IFP; however, in LS174T the MVP was significantly higher than the IFP. In conclusion, the results demonstrate that avascular tumors have atmospheric pressures and that tumor interstitial hypertension is associated with the development of the neovasculature.

Adenocarcinoma↗
PubMed1996

Effect of radiation on interstitial fluid pressure and oxygenation in a human tumor xenograft.

Elevated interstitial fluid pressure (IFP) is a pathophysiological characteristic of most human and experimental tumors and may be responsible, in part, for the poor distribution of blood-borne therapeutic agents and low blood flow rate in tumors. Recent data in cervical carcinomas in patients suggest that fractionated radiation can lower tumor IFP and increase oxygen partial pressure (pO (2)) in some patients. The goals of this study were to find the minimum dose of radiation required to modulate IFP and pO(2) and to determine the time course of IFP changes due to radiation in a preclinical model. Xenografts of the LS174T human colon adenocarcinoma were grown in the right flank of nude (BALB/c) mice. IFP and pO(2) were measured before and 24 h after graded doses of irradiation. The mean +/- SD initial IFP in untreated tumors was 12.9 +/- 0.5 mm Hg (n=109), and the range was 3.0 to 40.3 mm Hg. The mean +/- SD and median initial pO(2) were 20.2 +/- 2.4 and 11.9 mm Hg, respectively (n=37). IFP and pO(2) were independent of tumor size. Fractionated radiation lowered IFP by 2.5 mm Hg when the total dose was 10 or 15 Gy (P<0.05), but IFP did not change in the controls or the 5-Gy radiation group (P>0.05). Irradiation increased the proportion of tumors at higher oxygen tensions when compared to control tumors. The IFP and tumor volumes were followed for up to 10 days after a single dose of 10, 20, or 30 Gy of irradiation. IFP decreased for all treatment groups. The decrease was most significant for the group receiving 30 Gy. On day five following irradiation, the IFP had decreased by 35%. The changes in IFP and pO(2) occurred before any macroscopic changes in tumor volume could be observed. The radiation-induced decrease in IFP could be, in part, responsible for the increased uptake of monoclonal antibodies following single or fractionated radiation that has been reported in the literature.

Adenocarcinoma↗
PubMed1996

Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity.

Tumor blood flow (TBF) is characterized by spatial and temporal heterogeneities. Despite the crucial role of TBF in tumor growth, metastasis, and therapy, the mechanisms underlying these heterogeneities are not fully understood. Tumor vessels are, in general, more leaky than normal vessels and this may enhance the efficiency of fluid exchange between the vascular and the interstitial space. The coupling between transvascular fluid exchange and hemodynamics in tumors has not been explored previously. To investigate the role of transvascular fluid exchange on afferent and efferent blood flow, we modeled the tumor vasculature as an equivalent single vessel which is permeable and deformable and embedded in a fluid medium with uniform pressure. Simulations were carried out to examine the effects of vessel leakiness, vessel compliance, and interstitial fluid pressure on (a) pressure-flow relationship, (b) arterial-venous pressure relationship, and (c) pressure profile along the vessel. Experiments suggested by model simulations required an independent control of arterial and venous pressure and tumor blood flow. To this end, we perfused tissue-isolated tumors ex vivo and obtained data on perfusate flow rate vs arterial and venous pressures. The simulations predicted the following trends as a result of an enhanced fluid filtration across the vessel wall: (a) for a fixed arterial-venous pressure difference, efferent flow decreases with increasing venous pressure, (b) changes in venous pressure are not completely transmitted to the arterial side, and (c) the pressure profile along the vessel becomes less steep. The experimental results confirmed these trends and indicated that vascular and interstitial flow are coupled in isolated tumors. The implications of this coupling for the spatial and temporal heterogeneity in TBF are discussed.

Adenocarcinoma↗
PubMed1996

Environmental effects on laser Doppler pulpal blood-flow measurements in man.

The increasing number of experiments using laser Doppler flowmetry in man for pulpal blood-flow recordings leads to questioning of the experimental recording conditions. The present study focused on three points: the design of the laser probe holder, the isolation of the tooth, and the influence of the recording site. A rigid polyurethane splint used in addition to different isolation devices (cotton roll, metal shield, rubber dam) was compared with a silicone splint. The silicone resulted in significantly higher values (+341%) than the polyurethane splint. The combination of the polyurethane splint with isolation devices decreased, in all cases, the flux values. The polyurethane/rubber-dam combination was the most efficient in individualizing the pulpal blood flow (-69% decrease). Recordings on non-vital teeth confirmed the hypothesis that there was periodontal contamination of the recorded flow, as the signal was abolished when using the polyurethane/rubber-dam combination. Cervical recording sites gave significantly higher values than occlusal sites (+42%). It is concluded that, in man, the part played by the periodontium may have been underestimated in previous recordings of pulpal blood flow. The use of a rubber dam in combination with a rigid splint to enhance the validity of recordings is proposed.

Dental Pulp↗
PubMed1995

Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery.

Elevated interstitial fluid pressure (IFP) may constitute a significant physiological barrier to drug delivery in solid tumors. Strategies for overcoming this barrier have not been developed to date. To identify and characterize various mechanisms regulating IFP and to develop strategies for overcoming the IFP barrier, we modeled the tumor as a poroelastic solid. We used this model to simulate the effect of changes in microvascular pressure and tumor blood flow (TBF) on IFP. To test model predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in the center of an isolated tumor was predicted to follow variation of the arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally. Following a cessation of TBF, the time constant of the drop in IFP was predicted to be of the order of 1000 s and was found to be 1500 +/- 900 s experimentally. The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the interstitial matrix. Relying on the good agreement between theoretical predictions and experimental data, we estimated the effect of blood pressure modulation on macromolecular uptake in solid tumors. Our results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure. On the other hand, higher uptake would result from periodic modulation of blood pressure. Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.

Animals↗