Biomedical subjects

Y Boucher

Publications and source records attributed to Y Boucher.

At least 55 records · Page 3Linked to original sources

PubMed1995

Lack of general correlation between interstitial fluid pressure and oxygen partial pressure in solid tumors.

Several studies have shown a decrease in blood perfusion and oxygen partial pressure (pO2), and an increase in interstitial fluid pressure (IFP) with increasing tumor size. However, it is not evident if the elevated IFP is a key parameter responsible for the poor perfusion and oxygenation of solid tumors. To this end, IFP and pO2 were measured in nine human tumor xenografts in immunodeficient mice at a fixed tumor size (approximately 250 mm3). IFP and pO2 were also measured as a function of tumor volume in one human colon adenocarcinoma (LS174T) and in one human glioblastoma (HGL-9). In LS174T tumors IFP did not vary with size (P < .07); however, median pO2 decreased from approximately 35 mm Hg in 100-mm3 tumors to approximately 15 mm Hg in tumors of approximately 500 mm3 (P < 0.001). In HGL-9 tumors an inverse correlation between IFP and pO2 was found; IFP increased (P < 0.001) and pO2 decreased (P < 0.001) with increasing tumor size. At a fixed tumor size of 250 mm3 no correlation was found between mean IFP and median pO2 (P < 0.5) or between the mean IFP and the hypoxic fraction (pO2 < 2.5 mm Hg) (P < 0.7) in the nine tumors studied. The absence of a general relationship between IFP and pO2 could result in part from differences in vascular resistance between tumors. For example, a high geometric resistance to blood flow on the arterial side will lead to a low IFP and blood flow, whereas an elevation of the venous resistance will reduce blood flow and increase IFP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation.

Various vasoactive agents have been used to modify tumor blood flow with the ultimate goal of improving cancer detection and treatment, with widely disparate results. Furthermore, the lack of mechanistic interpretations has hindered understanding of how these agents affect the different physiological parameters involved in perfusion. Thus, there is a need to develop a unified framework for understanding the interrelated physiological effects of pharmacological and physical agents. The goals of this study were (1) to develop a mathematical model which helps determine the location and magnitude of changes in the vascular resistance of tumor and normal tissues and (2) to test the model with our experimental studies and by comparison with results from the literature. The systemic and interstitial pressures and relative tumor blood flow were measured before and after administration of angiotensin II, epinephrine, norepinephrine, nitroglycerin, and hydralazine in SCID mice bearing LS174T human colon adenocarcinoma xenografts. A mathematical model was developed in analogy to electrical circuits which examined the pressure, flow, and resistance relationships for arterial and venous segments of the vasculature of a tumor and surrounding normal tissue. Vasoconstrictor-induced increases in the mean arterial blood pressure led to increases in tumor blood flow and interstitial pressure with the magnitude of change dependent on the agent (percentage change in blood flow: angiotensin > epinephrine > norepinephrine). The vasodilating agents induced decreases in tumor blood flow in parallel to the induced decreases in the systemic pressure, but only the long-acting arterial vasodilator hydralazine was capable of effecting a decrease in tumor interstitial pressure. The model was also found to be consistent with other data available in the literature on norepinephrine, pentoxifylline, nicotinamide, and hemodilution, and was useful in providing input as to the location and degree of the physiological effects of these agents. The results of the data and model show that the steal phenomenon is the dominant mechanism for redistribution of host blood flow to the tumor. However, some degree of arterial control was found to be present in the tumors. Moreover, the parallel increases in tumor interstitial pressure and blood flow contradict any hypothesis suggesting that elevated interstitial fluid pressure precipitates chronic vascular collapse, thus decreasing blood flow.

Angiotensin II↗

PubMed1994

Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows.

Many brain tumors are highly resistant to chemotherapy, presumably due to the presence of a tight blood-tumor barrier. For a better understanding of the regulation of this barrier by the brain environment, a new intravital microscopy model was established by transplanting tumor tissue into cranial windows in both rats and mice. The model was characterized by RBC velocities, vessel diameters, and vascular permeabilities of various tumors: R3230AC (a rat mammary adenocarcinoma), MCaIV (a mouse mammary adenocarcinoma), and U87 and HGL21 (human malignant astrocytomas). Our results showed that tumor blood flow in cranial windows was one to three orders of magnitude lower than the blood flow in pial vessels and similar to that in dorsal skin-fold chambers observed in previous studies. The mean vessel diameter ranged from 6.8 +/- 1.3 microns for HGL21 to 30.4 +/- 8.5 microns for MCaIV. At least one order of magnitude difference in vascular permeability to albumin was observed between tumor lines: 0.11 +/- 0.05 x 10(-7) cm/s for HGL21 versus 3.8 +/- 1.2 x 10(-7) cm/s for U87. The low vascular permeability of HGL21, which was also confirmed by both sodium fluorescein and Lissamine green injections, suggests that not all tumors are leaky to tracer molecules and that the blood-tumor barrier of this tumor still possesses some characteristics of blood-brain barrier as observed in other intracranial tumors. The model presented here will allow us to manipulate the vascular permeability in brain tumors and thus may provide new information on the regulation of the blood-tumor barrier and new strategies for improving drug delivery in brain tumors.

Animals↗

PubMed1994

Effect of hemodilution and resuscitation on tumor interstitial fluid pressure, blood flow, and oxygenation.

Hemodilution due to hemorrhage may increase tumor blood flow (TBF) by lowering blood viscosity and decrease tumor interstitial fluid pressure (TIFP) by moving fluid from the interstitium to the vascular compartment and by lowering microvascular pressure (MVP), mainly due to the decrease in systemic pressure. To test this hypothesis, we measured mean arterial blood pressure (MABP), TIFP, hematocrit, relative TBF (RBC flux), and intratumor pO2 during hemorrhage and volume restitution in severe combined immunodeficient mice, bearing LS174T human colon adenocarcinoma xenografts. MABP and TIFP significantly decreased after 0.2 ml of blood (approximately 12% of blood volume) was withdrawn. MABP decreased from 87.5 +/- 3.9 mmHg (mean +/- standard error) to 59.8 +/- 4.8 mmHg (n = 5, P = 0.01) within 2.5 min after the withdrawal of blood and then returned to control value within 10 min. TIFP gradually decreased from 18.7 +/- 2.3 mmHg to 11.3 +/- 0.9 mmHg after 1 hr (n = 8, P = 0.01), while RBC flux increased by a factor of 1.99 +/- 0.38 (n = 5, P = 0.02). The systemic hematocrit decreased from 51.2 to 45.9% (n = 7, P = 0.02). Tumor oxygenation did not significantly improve (median pO2 for control, 28 mmHg, and median pO2 after blood withdrawal, 32 mmHg; P = 0.14). When 0.2 ml blood was withdrawn and replaced (within 2.5 min) with the same volume of normal saline, MABP significantly decreased from 86.4 +/- 2.4 mmHg to 65.6 +/- 4.6 mmHg (n = 11) at 1 hr post-treatment (P = 0.001). TIFP decreased, but not significantly, from 24.2 +/- 2.9 mmHg to 20.4 +/- 2.4 mmHg (P = 0.35). Blood withdrawals in excess of 0.3 ml significantly decreased MABP and TIFP without recovery during 1 hr of observation. Volume restitution with hyperoncotic/hyperosmotic 6.0% Dextran 70 and 7.5% saline had effects attributable to a direct transmission of systemic pressure to the tumor microcirculation and to a lowering of tumor venous resistance. These effects appear to be common to saline blood restitution and volume top-load with Dextran 70. In conclusion, mild hemorrhage (withdrawal of approximately 12% of blood volume) can significantly lower TIFP without a reduction in TBF and pO2.

Adenocarcinoma↗

PubMed1994

Changes in tumour blood flow, oxygenation and interstitial fluid pressure induced by pentoxifylline.

Pentoxifylline (PTX) has been shown to increase radiation damage to tumours and to decrease late radiation-induced injury to normal tissues. This tumour radiation sensitisation results from increased oxygen supply via improved tumour perfusion. We propose that the improved perfusion results from decreased viscous resistance and/or geometric resistance. The decreased flow resistance may be accompanied by a reduction in microvascular pressure (MVP). Since MVP is approximately equal to the interstitial fluid pressure (IFP), PTX should lead to a decrease in IFP. To test this hypothesis, we measured PO2, laser Doppler flow (RBC flux) and IFP in FSaII murine tumours at two doses (PTX at 25 and 100 mg per kg body weight) which sensitise this tumour to X-irradiation. We found that 25 mg kg-1 PTX was ineffective, but 100 mg kg-1 PTX was effective in increasing the PO2 of this tumour. PTX at 100 mg kg-1 (i.p.) increased median PO2 from 5 to 7 mmHg (P < 0.05) within 2 h, and decreased the fraction of PO2 values < 5 mmHg from 65% to 45% (P < 0.05). In support of our hypothesis, we found that with this dose of PTX, RBC flux in the tumour centre increased significantly (n = 6, P < 0.05) prior to an approximately 40% decrease (n = 13, P < 0.05) in tumour interstitial fluid pressure (TIFP), without changes in mean arterial blood pressure (MABP). In conclusion, a single i.p. administration of PTX at 100 mg kg-1 can increase oxygen availability in the tumour due to ameliorate hypoxia in tumour microregions. Second, PTX can lower the elevated TIFP without lowering the MABP.

Animals↗

PubMed1993

Dexamethasone reduces the interstitial fluid pressure in a human colon adenocarcinoma xenograft.

The effect of dexamethasone on interstitial hypertension was evaluated in a human colonic adenocarcinoma. Two weeks after transplantation of the tumor line LS174T into SCID mice, recipients with tumors > 8.5 mm in diameter received one daily injection i.p. on days 1-4, at five different doses in the range of 0.3-30 mg/kg. Controls received saline. The interstitial fluid pressure (IFP) was determined in all tumors pretherapeutically on days 1, 4, and 7. A total of 68 tumors were examined, and in an additional group of 22 mice, the effect of 4-day dexamethasone therapy on blood pressure was evaluated. In the 3-, 10-, and 30-mg/kg dose groups a significant reduction in IFP was found, comparing treated versus controls and individual measurements from day 1 versus day 4. No effects were observed on day 7. A marginal effect was observed after 1.0 mg/kg, whereas 0.3 mg/kg did not affect the IFP. The systemic blood pressure was slightly increased by the dexamethasone therapy, and no treatment related changes in tumor sizes were observed. Our findings indicate that the reversible decrease in tumor IFP by dexamethasone is an effect of a reduced microvascular permeability and vascular hydraulic conductivity in the tumors.

Adenocarcinoma↗

PubMed1993

Microinfusions of excitatory amino acid antagonists into the trigeminal sensory complex antagonize the jaw opening reflex in freely moving rats.

Microinfusions of EAA antagonists (APV 0.1 microliter 25 mM, gamma-DGG 0.1 microliter 50 mM, CNQX 0.1 microliter 50 mM, ketamine 0.1 microliter 0.2 M) were performed in freely moving rats while recording the long latency jaw opening reflex (JOR) elicited by electrical stimulation of the dental pulp. NMDA and non-NMDA antagonists were applied in the trigeminal sensory complex at the termination of dental pulp afferents. The selective NMDA antagonist APV strongly reduced the amplitude of the polysynaptic JOR. gamma-DGG and ketamine, which are broader spectrum NMDA antagonists, showed similar effects with some variations in their kinetics. CNQX, an antagonist for non-NMDA receptor subtypes, failed to affect the JOR. The results suggest that long latency JOR requires activation of NMDA receptors, while the early component elicited by periodontal afferents does not. These NMDA-receptors could belong either to JOR interneurons activated by tooth pulp afferents or to digastric motoneurons, receiving the inputs through a polysynaptic pathway. Recent anatomical results favour the first hypothesis while not excluding the second.

2-Amino-5-phosphonovalerate↗

PubMed1993

Effect of angiotensin II induced hypertension on tumor blood flow and interstitial fluid pressure.

The effect of angiotensin II-induced hypertension on tumor interstitial fluid pressure (TIFP) and tumor blood flow (TBF) was investigated to examine blood flow and pressure regulation in solid tumors. TIFP measurements were made before and after administration of angiotensin II using the wick-in-needle method in s.c. tumor implants. Relative TBF was continuously monitored by laser doppler velocimetry. The effect of host strain on TIFP was evaluated in MCA-IV mammary carcinoma, transplanted in C3H and SCID mice, and showed no significant difference. The effects of tumor types were evaluated by comparing two murine tumors, MCA-IV mammary carcinoma and FSaII fibrosarcoma, and a human tumor xenograft, LS174T adenocarcinoma, transplanted in SCID mice. Baseline TIFP was elevated in all three tumor lines to significantly different pressures. AII-induced hypertension (approximately 150 mm Hg) had a variable but tumor line-specific effect on TIFP and TBF. The increase in TIFP was correlated with the baseline TIFP (r2 = 0.853) (increasing from 6.9 to 8.7 mm Hg, 10.5 to 15.8 mm Hg, and 21.7 to 29.4 mm Hg in FSaII, MCA-IV, and LS174T, respectively). These data suggest that in addition to blood flow redistribution due to the steal phenomenon, arterial control of TBF and TIFP exists within these solid tumors; however, the extent of control is tumor line dependent and less than that in normal tissues. Moreover, parallel increases in TIFP and TBF do not support the hypothesis that elevated TIFP causes vascular collapse and thus decreases TBF.

Adenocarcinoma↗

PubMed1992

Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice.

To date, most quantitative information on tumor angiogenesis, microcirculation, and transport has been derived from rodent tumors grown in transparent chamber preparations. In this paper we present a chamber technique adapted to immunodeficient mice for the study of human tumor xenografts. Microcirculatory parameters in severe combined immunodeficient mice bearing a dorsal skin fold chamber preparation were quantified using intravital microscopy and image analysis. The take rate of the human colon adenocarcinoma LS174T in the chamber preparation was 100%, and the tumor area doubling time was 6.5 days. Three days following implantation of 2 x 10(5) tumor cells onto the striated skin muscle, capillary sprouts were noted in the tumor cell mass. Microvasculature in the tumors was established after 10 days. Capillary density, vessel diameter, red blood cell velocity, and blood flow rates in individual microvessels measured on days 10, 14, 18, and 22 showed no statistical difference in the striated muscle (capillaries) and subcutaneous tissue (arterioles and venules) of the skin of tumor-free animals (N = 6), whereas these parameters increased slightly, but not significantly, in the LS174T tumors (N = 7). Mean interstitial fluid pressure (+/- SD) in these small tumors was 4.6 +/- 1.7 mmHg (N = 4) on day 10 and 5.1 +/- 0.9 mmHg (N = 4) on day 22 and significantly elevated compared to that in the subcutaneous and skin tissue (-0.9 +/- 0.8 mmHg) (N = 4) (P < 0.001). To our knowledge, this is the first model enabling intravital microscopic studies of human tumor xenografts in a transparent chamber preparation in severe combined immunodeficient mice. Studies on angiogenesis, microcirculation, and transport using such a preparation should provide new insights into microcirculation-mediated mechanisms for cancer treatment.

Adenocarcinoma↗

PubMed1992

Interstitial hypertension in human breast and colorectal tumors.

The efficacy of present day antineoplastic regimens depends upon the delivery and penetration of therapeutic agents through the tumor vascular and interstitial spaces to the tumor cell target. The distribution of relevant molecules or cells in a solid tumor is often poor and heterogeneous and is believed to be due to a number of pathophysiological factors, including elevated interstitial fluid pressure (IFP). Using the wick-in-needle technique, IFP was measured in primary breast and colorectal carcinomas as well as their respective metastases to the lymph nodes and liver in a total of 17 patients. IFP was also measured in one recurrent renal cell carcinoma, one melanoma metastasis to the lymph nodes, and another melanoma metastasis to the lung. IFP varied from 4 to 50 mm Hg with a mean +/- SD of 20 +/- 13 mm Hg in the neoplasms (n = 41 measurements; n = 21 tumors), while IFP in normal tissues had a mean of 2 +/- 4 mm Hg (n = 11). The mean IFPs for metastatic melanoma, primary breast carcinoma, and liver metastases from a colorectal primary were found to be 33 +/- 14, 15 +/- 9, and 21 +/- 12 mm Hg, respectively. In the renal cell carcinoma, the pressure was 38 mm Hg. These results agree with the findings of our 3 previous studies examining IFP in human superficial melanomas (14.3 +/- 12.5 mm Hg, n = 12), cervical carcinomas (15.7 +/- 5.7 mm Hg, n = 12), and head and neck tumors (13.2 +/- 8.8 mm Hg, n = 19), and indicate that in all types of human tumors studied to date, IFP was significantly elevated above that of normal tissue. This observation may be useful in localizing tumors during needle biopsy.

Adult↗

PubMed1992

Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse.

The interstitial fluid pressure (IFP) has been found to be as high as 20 to 50 mm Hg in both experimental and human solid tumors. While the IFP is an important determinant of the delivery of therapeutic agents to neoplastic cells in vivo, the mechanisms responsible for interstitial hypertension are not completely understood. The high vascular permeability of tumor blood vessels and the absence of a functional lymphatic circulation suggest that the hydrostatic microvascular pressure (MVP) is the main force governing IFP in tumors. To test this hypothesis, we simultaneously measured IFP and MVP in 13 tissue-isolated R3230AC mammary adenocarcinomas transplanted in rats. The MVP in superficial postcapillary venules of diameters between 25 and 250 microns was measured with the micropuncture technique. MVP was compared to the IFP in the periphery (measured with micropuncture technique) and in the center (measured with wick-in-needle technique). Similar to our previous study, IFP rose rapidly and reached maximum values at a depth of 0.2 to 1.0 mm from the tumor surface. These maximum IFP values [16.5 +/- 7.1 mm Hg (SD)] were equal to IFP in the tumor center [18.4 +/- 9.3 mm Hg] [R2 = 0.86, P greater than 0.8]. Superficial MVP (17.3 +/- 6.1 mm Hg) was equal to both central (P greater than 0.9) and superficial IFP (P greater than 0.7). These results demonstrate that the main driving force for IFP in tumors is the MVP. Furthermore, the concept that blood vessel collapse is induced by higher hydrostatic pressures in the tumor interstitium compared to that in the vascular lumen is not supported by the present finding that elevated IFP is accompanied by equally elevated MVP.

Adenocarcinoma↗

PubMed1992

Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications.

Several investigators have shown that nicotinamide (NA) may increase the tumor blood flow and/or alleviate temporal fluctuations in tumor blood flow and, consequently, increase pO2. However, the mechanisms of these changes in tumor blood flow are not understood, especially because NA lowers the mean arterial blood pressure in mice. Our hypothesis is that NA may decrease flow resistance in tumors, which would lower vascular pressure and tumor interstitial fluid pressure (TIFP). To test this hypothesis, we measured the physiological parameters: mean arterial blood pressure, TIFP, tumor water content, and hematocrit in C3H mice bearing FSaII tumors, before and after treatment with 500 mg/kg of NA. In control animals, TIFP increased with tumor growth up to 400 mm3, reached a plateau, and then decreased when the tumor size was above 1000 mm3 (n = 135). Tumor water content correlated significantly with TIFT (for tumors less than 500 mm3) (n = 26). NA caused approximately a 15% decrease in mean arterial blood pressure (P less than 0.05) and a 35% decrease in TIFP (P less than 0.001) at 2 h postinjection, without any change in hematocrit. The change in TIFP was found to be tumor size dependent. Specifically, NA decreased the TIFP by 47% (P less than 0.001) and 39% (P less than 0.001) in medium (200 to 500 mm3) and large (500 to 800 mm3) tumors, respectively. The decrease in TIFP in small (less than 200 mm3) and very large (greater than 800 mm3) tumors was not statistically significant (P greater than 0.1). Our results may explain the size-dependent enhancement in pO2 and radiation response reported by I. Lee and C. W. Song (Radiat. Res., 130: 65-71, 1992) for this tumor line. If our results could be confirmed in human tumors in situ, they would have significant implications in noninvasive measurements of TIFP using NMR and in cancer treatment using radiation, chemotherapy, and immunotherapy.

Animals↗

PubMed1992

Preoperative and long-term cardiac risk assessment. Predictive value of 23 clinical descriptors, 7 multivariate scoring systems, and quantitative dipyridamole imaging in 360 patients.

A total of 360 patients underwent preoperative cardiac risk assessment using 23 clinical parameters, seven multivariate clinical scoring systems, and quantitative dipyridamole-thallium imaging to predict postoperative and long-term myocardial infarction and cardiac death after noncardiac surgery. There were 30 postoperative and an additional 13 cumulative long-term cardiac events after an average follow-up of 15 months. Clinical descriptors were not useful in predicting the outcome of individual patients. The postoperative and long-term cardiac event rates were 1% and 3.5%, respectively, in patients with normal scans or fixed perfusion defects, and 17.5% and 22% in patients with reversible defects. Using quantitative indices reflecting the amount of jeopardized myocardium, patients could be stratified by dipyridamole imaging into multiple scintigraphic subsets, with corresponding postoperative and 1-year coronary morbidity and mortality rates ranging from 0.5% to 100% (p = 0.0001). Thus, postoperative and long-term cardiac events cannot be predicted clinically, whereas quantitative dipyridamole imaging accurately identifies high-risk patients who require preoperative coronary angiography.

Aged↗

PubMed1992

Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double-phase study)

Dual radionuclide imaging using a combination of 201Tl with either 99mTcO4- or 123I is recognized as a useful procedure in the preoperative localization of parathyroid adenomas. Recently, 99mTc-sestamibi (MIBI) has been introduced for myocardial perfusion imaging as an alternative to 201Tl. The purpose of this prospective study was to evaluate parathyroid scan using early and late imaging following MIBI injection. Twenty-three patients (21 F, 2 M, mean age: 57 yr) with a clinical and biologic diagnosis of hyperparathyroidism were submitted to a MIBI study prior to surgical exploration of the neck. Cervico-thoracic planar imaging (anterior view, 10 min/view) was performed at 15 min and at 2-3 hr after an intravenous injection of 20-25 mCi of MIBI. A positive MIBI scan for parathyroid adenoma was defined as an area of increased focal uptake which persisted on late imaging, contrary to the uptake in the normal thyroid tissue which progressively decreases over time (differential washout). Surgical exploration of the neck, performed between 1 day and 72 days (average: 16 days) after the MIBI study, showed a parathyroid adenoma in 21 patients and hyperplasia in two patients. MIBI scan correctly detected and localized 19/21 adenomas (90%). In conclusion, parathyroid imaging using a single radionuclide with MIBI (early and late study with differential washout analysis) is a promising procedure in the preoperative detection and localization of parathyroid adenomas in patients with primary hyperparathyroidism.

Adenoma↗

PubMed1992

[Demonstration of glutamate in primary sensory trigeminal neurons innervating dental pulp in rats].

Primary sensory trigeminal neurons supplying the dental pulp of incisors in rats were labelled by retrograde axonal transport. Using an auto-metallographic intensification procedure, 48 hrs. after injection of wheat-germ colloidal gold in the pulp, gold particles were detected in the cytoplasm of the neurons as black granulations. Glutamate was found in 45-60% of the neurons by submitting ganglion slices to an anti-glutamate immuno-serum revealed by immunocytochemistry. Among the neurons supplying the dental pulp of incisors by their peripheral process, 70% are Glu+, 30% Glu-. These observations suggest that the population of neurons supplying the dental pulp is not functionally homogeneous and that Glu- neurons use a different neurotransmitter. The coexistence of Glu+ and Glu- neurons could also indicate that glutamate expression is modulated during the life of these neurons.

Animals↗

PubMed1991

Interstitial hypertension in superficial metastatic melanomas in humans.

Since 1950, several investigators have demonstrated that interstitial hypertension is a pathophysiological characteristic of experimental solid tumors. To date, interstitial fluid pressure (IFP) has not been measured in human tumors in situ. In this study we measured with the wick-in-needle technique the interstitial fluid pressure in superficial melanoma metastases (n = 12) in patients (n = 10) before and during systemic therapy. In the majority of tumors the pressure was found to be almost uniform, while in others it varied severalfold. The large variations in IFP in some tumors may be due to technical or biological factors. With the data obtained before and during therapy grouped, the mean IFP in melanoma lesions varied between 2 and 41 mm Hg with an overall mean of 14.3 +/- 12.5 (SD). IFP was found to be significantly higher (P less than 0.01) in large (22.8 +/- 13 mm Hg; n = 6) than in small (5.8 +/- 2mm Hg; n = 6) lesions. This study demonstrates that IFP can be measured in human tumors using the wick-in-needle technique and that the pressure in some of the large melanomas exceeds the values measured to date in rodent tumors or human tumor xenografts. The latter result suggests that caution must be exercised in extrapolating values of pathophysiological parameters from transplanted tumors to human tumors.

Adult↗

PubMed1991

Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response.

Elevated tumor interstitial fluid pressure (IFP) is believed to be responsible, at least in part, for the poor penetration and heterogeneous distribution of blood-borne therapeutic agents and nutrients in solid tumors. Using the wick-in-needle technique, IFP was measured in human patients with squamous cell carcinoma of the uterine cervix at the initial and final stages of fractionated external beam radiotherapy. Mean IFP values ranged from 10 to 26 mm Hg with an overall mean of 15.7 +/- 5.7 (SD) mm Hg in stage IIB and IIIB tumors (n = 12) and from 0 to 3 mm Hg in normal cervix (n = 3). IFP decreased in some patients with therapy while in others it increased. The changes in IFP values agree well with the clinical response to radiotherapy (n = 7, P less than 0.05). Oxygen tension, measured in selected tumors (n = 3) with polarographic oxygen microelectrodes, inversely correlated with IFP. These results show for the first time that the IFP in human cervical carcinomas is elevated, and that it can be lowered in some tumors using fractionated radiation therapy. These findings also suggest that IFP values may provide an indication of tumor oxygenation and that IFP modifications could be prognostic indicators of radiation response.

Adult↗

PubMed1990

Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy.

High interstitial fluid pressure (IFP) in solid tumors is associated with reduced blood flow as well as inadequate delivery of therapeutic agents such as monoclonal antibodies. In the present study, IFP was measured as a function of radial position within two rat tissue-isolated tumors (mammary adenocarcinoma R3230AC, 0.4-1.9 g, n = 9, and Walker 256 carcinoma, 0.5-5.0 g, n = 6) and a s.c. tumor (mammary adenocarcinoma R3230AC, 0.6-20.0 g, n = 7). Micropipettes (tip diameters 2 to 4 microns) connected to a servo-null pressure-monitoring system were introduced to depths of 2.5 to 3.5 mm from the tumor surface and IFP was measured while the micropipettes were retrieved to the surface. The majority (86%) of the pressure profiles demonstrated a large gradient in the periphery leading to a plateau of almost uniform pressure in the deeper layers of the tumors. Within isolated tumors, pressures reached plateau values at a distance of 0.2 to 1.1 mm from the surface. In s.c. tumors the sharp increase began in skin and levelled off at the skin-tumor interface. These results demonstrate for the first time that the IFP is elevated throughout the tumor and drops precipitously to normal values in the tumor's periphery or in the immediately surrounding tissue. These results confirm the predictions of our recently published mathematical model of interstitial fluid transport in tumors (Jain and Baxter, Cancer Res., 48: 7022-7032, 1988), offer novel insight into the etiology of interstitial hypertension, and suggest possible strategies for improved delivery of therapeutic agents.

Adenocarcinoma↗