History of burning mouth syndrome (1800-1950): A review.

This medical history historic literature review aims at understanding the evolution of the medical existence of burning mouth syndrome (BMS) over times. Three historic research tools were used (Medic@, IndexCat, Gallica) with several keywords, exploring the years 1800-1950. One hundred and fifty documents were obtained dating from 1803 to 1937, including 55 reviews, 44 original articles, 40 quotations, and 11 medical dictionaries. A total of 199 cases of BMS were reported which allowed for a narrative review of the early history of BMS (1800-1950). This review spans from the description of the first clinical cases by several authors in Europe to the creation of the syndrome by the French Academy of Medicine, its intellectual sponsorship by the emerging discipline of neuropsychiatry, to its subsequent evolution until the conceptual shift of the American authors. A better knowledge of the evolution of the nosology of BMS throughout history should bring a better understanding of current approaches for treating such an affection.

Taste function assessed by electrogustometry in burning mouth syndrome: a case-control study.

OBJECTIVE: Idiopathic burning mouth syndrome (iBMS) is characterized by oral persistent pain without any clinical or biological abnormality. The aim of this study was to evaluate taste function in iBMS subjects and healthy controls. MATERIAL AND METHODS: Electrogustometric thresholds (EGMt) were recorded in 21 iBMS patients and 21 paired-matched controls at nine loci of the tongue assessing fungiform and foliate gustatory papillae function. Comparison of EGMt was performed using the nonparametric Wilcoxon signed-rank test. A correlation between EGMt and self-perceived pain intensity assessed using a visual analogic scale (VAS) was analyzed with the Spearman coefficient. The level of significance was fixed at P < 0.05. RESULTS: Mean EGMt were significantly increased with iBMS for right side of the dorsum of the tongue and right lateral side of the tongue (P < 0.05). In the iBMS group, VAS scores were significantly correlated to EGMt at the tip of the tongue (r = -0.59; P < 0.05) and at the right and left lateral sides of the tongue (respectively, r = -0.49 and r = -0.47; P < 0.05). CONCLUSION: These data depicted impaired taste sensitivity in iBMS patients within fungiform and foliate taste bud fields and support potent gustatory/nociceptive interaction in iBMS.

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.

[Radiographic study of the canal anatomy of mandibular premolars in a Senegalese population]. / Etude radiographique de l'anatomie canalaire des premolaires mandibulaires dans une population Senegalaise.

AIM: The purpose of this study was to assess the canal anatomy of mandiblar premolars in Senegalese population. MATERIALS AND METHODS: Retroalveolar radiographs of mandibular premolars of 208 patients in Senegal were obtained. Two experienced practitioners using a long cone tube and the parallel plane technique with angulators took the radiographs. The canal morphology of each tooth was determined in terms of the number of canals radiologically visible to the apex. Any anatomic structure emanating from the pulp chamber or the principal canal to the apex and measuring more than 3 millimetres was considered to be a supplementary canal. RESULTS: For the 208 patients studied, 412 first premolars were present and 4 were absent.Among the 412 teeth, 335 (81.3%) had a single canal, 62 (15.1%) 2 canals, and 17 (3.6%) 3 canals. For the second premolars 408 were present. Of the 408 teeth, 352 (86%) had one canal, 49 (12%) 2 canals, and 8 (2%) 3 canals. CONCLUSION: The prevalence of two or more canals in premolar mandibular from Senegalese patients was similar to that found in the others ethnic population.

[Prevalence of fixed prosthesis-related periodontitis in Senegal]. / Prévalence de la prothèse fixèe et des parodontites apicales associées au Sénégal.

The purpose of this study was to determine radiographically the prevalence of periapical periodontitis in teeth restored with crown in a Senegalese population. Full mouth periapical radiographs were obtained from 208 consecutive adult patients (6234 teeth) presenting as new patients to the Dental Service of the University. The presence of crown restorations, the periapical status and technical quality of root fillings associated were evaluated. 7.69% (n = 16) of patients had at least one tooth that was crowned. The total number of crowns assessed was 0.95% (n = 59). The molars were the teeth most crowned 40.67% (n = 24) followed by anterior teeth 30.50% (n = 18) and premolars 28.81% (n = 17). All the crowned teeth had previous root canal treatment of which only 16.94% (n = 10) were acceptable. 53 % (n = 32) of the teeth had apical periodontitis (PAI > 2). Unacceptable root fillings were associated with a higher prevalence of periapical disease (p < 0.05). Crown with a post extending more than 4 millimetres from the apex were associated with more periapical lesions 64.28% (p < 0.05). The results indicate a low prevalence of crowned teeth, an absence of vital preparation, a high prevalence of radiographic periapical disease and unacceptable root fillings associated.

Neuropathic pain in the orofacial region: The role of pain history. A retrospective study.

INTRODUCTION: Orofacial neuropathic pain is often difficult to treat, mostly because of still unclear underlying mechanisms. The occurrence of such neuropathic pain varies depending on different factors, of which preexisting preoperative pain seems to be of high importance. The aim of this study was thus to test the hypothesis that prior history of pain could indeed be considered a risk factor for the development of orofacial neuropathic pain in the same region. METHODS: The study was performed in the dental department of the Groupe Hospitalier Pitié-Salpêtrière (GHPS) in Paris, France. We investigated the presence of prior inflammatory pain before development of orofacial neuropathic pain in 56 patients. For each patient file, the following items were collected: age, gender; medical history; diagnosis; description of the pain (at time of consultation); presence or absence of prior dental treatment; date and type of dental treatment received. RESULTS: 41 patients (73%) of orofacial neuropathic pain patients had a history of pain compatible with an inflammatory condition; 4% (n=2) did not report any prior pain and 23% (n=13) could not remember. Among the patients with documented history of pain prior to neuropathy, 88% (n=36) received surgical treatment; 61%, (n=25) endodontic treatment and 22%, (n=9) restorative treatment. All eventually received endodontic treatment or tooth extraction. These dental treatments are compatible with the hypothesis of prior inflammatory pain in these patients. CONCLUSION: These results support the hypothesis that prior inflammatory pain could favor the development of orofacial neuropathic pain. Prevention and treatment of inflammatory trigeminal pain may therefore play a key role in preventing future neuropathic pain development.

Hedgehog Pathway-Mediated Vascular Alterations Following Trigeminal Nerve Injury.

Whereas neurovascular interactions in spinal neuropathic pain models have been well characterized, little attention has been given to such neurovascular interactions in orofacial neuropathic pain models. This study investigated in male Sprague-Dawley rats the vascular changes following chronic constriction injury (CCI) of the infraorbital nerve (IoN), a broadly validated preclinical model of orofacial neuropathic pain. Following IoN-CCI, an early downregulation of tight junction proteins Claudin-1 and Claudin-5 was observed within the endoneurium and perineurium, associated with increased local accumulation of sodium fluorescein (NaFlu) within the IoN parenchyma, as compared with sham animals. These events were evidence of local blood-nerve barrier disruption and increased vascular permeability. A significant upregulation of immunocytes (CD3, CD11b) and innate immunity (TLR2, TLR4) mRNA markers was also observed, suggestive of increased local inflammation. Finally, a significant downregulation of Hedgehog pathway readouts Patched-1 and Gli-1 was observed within the IoN after CCI and local injections of cyclopamine, a Hedgehog pathway inhibitor, replicated in naïve rats the molecular, vascular, and behavioral changes observed following IoN-CCI. These results suggest a major role of Hedgehog pathway inhibition in mediating local increased endoneurial and perineurial vascular permeability following trigeminal nerve injury, thus facilitating immunocytes infiltration, neuroinflammation development, and neuropathic pain-like aversive behavior.

Microbial genomes: dealing with diversity.

We have now complete genome sequences of several pairs of closely related prokaryotes (conspecific strains or congeneric species). Surprisingly, even strains of the same species can differ by as much as 20% in gene content. Conceptual and methodological approaches for dealing with such diversity are now being developed, and should transform microbial genomics.

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.

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.

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.

Oncotic pressure in solid tumors is elevated.

Oncotic and hydrostatic pressure differences control the movement of fluid and large molecules across the microvascular wall of normal and tumor tissues. Recent studies have shown that the interstitial fluid pressure in tumors is elevated and is approximately equal to the microvascular pressure. Whereas oncotic pressure in blood plasma of various species is known, no data are available on the oncotic pressure in the interstitial space of tumors. We hypothesize that because of the leaky nature of tumor vessels, oncotic pressure in tumor interstitium should be close to that in plasma. To this end, we first developed a chronic wick method for the direct measurement of oncotic pressures in the interstitial fluid of tumors grown in mice. We found interstitial oncotic pressures in four human tumor xenografts to be higher than in s.c. tissue and comparable to that in plasma [rhabdomyosarcoma (RD), 24.2+/-4.7; squamous cell carcinoma (FaDu), 19.9+/-1.9; small cell lung carcinoma (54A), 21.1+/-2.8; colon adenocarcinoma (LIS174T), 16.7+/-3.0 mm Hg; s.c. tissue, 8.2+/-2.3; plasma, 20.0+/-1.6 mm Hg]. These results support our hypothesis that the oncotic pressure difference across the tumor microvascular wall is low. The high oncotic pressure in tumors is consistent with the elevated interstitial fluid pressure, and it contributes to the suboptimal delivery of large therapeutic agents to neoplastic cells.

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.

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.

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.

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.

Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts.

Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic.

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.

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.

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.