Interstitial Fluid Pressure Measurements Research Articles

Effect of interstitial fluid pressure on shear wave elastography: an experimental and computational study

Objective. An elevated interstitial fluid pressure (IFP) can lead to strain-induced stiffening of poroelastic biological tissues. As shear wave elastography (SWE) measures functional tissue stiffness based on the propagation speed of acoustically induced shear waves, the shear wave velocity (SWV) can be used as an indirect measurement of the IFP. The underlying biomechanical principle for this stiffening behavior with pressurization is however not well understood, and we therefore studied how IFP affects SWV through SWE experiments and numerical modeling. Approach. For model set-up and verification, SWE experiments were performed while dynamically modulating IFP in a chicken breast. To identify the confounding factors of the SWV-IFP relationship, we manipulated the material model (linear poroelastic versus porohyperelastic), deformation assumptions (geometric linearity versus nonlinearity), and boundary conditions (constrained versus unconstrained) in a finite element model mimicking the SWE experiments. Main results. The experiments demonstrated a statistically significant positive correlation between the SWV and IFP. The model was able to reproduce a similar SWV-IFP relationship by considering an unconstrained porohyperelastic tissue. Material nonlinearity was identified as the primary factor contributing to this relationship, whereas geometric nonlinearity played a smaller role. The experiments also highlighted the importance of the dynamic nature of the pressurization procedure, as indicated by a different observed SWV-IFP for pressure buildup and relaxation, but its clinical relevance needs to be further investigated. Significance. The developed model provides an adaptable framework for SWE of poroelastic tissues and paves the way towards non-invasive measurements of IFP.

Review on the Lymphatic Vessels in the Dental Pulp.

Simple SummaryIt is debatable whether lymphatic vessels exist in the dental pulp. Most researchers confirm their presence; however, the lymphatic system in the dental pulp is much less developed compared to other tissues of the body. Lymphangiogenesis occurs in the dental pulp with inflammatory changes as a response to inflammatory stimuli acting on the tooth. If lymphangiogenesis is defined as the development of lymphatic vessels from already existing ones, such a mechanism is possible only when lymphatic vessels are present in healthy teeth. Research papers have not conclusively proved whether lymphatic vessels can form in the dental pulp. The use of an immunohistochemical examination can very likely prove the presence of a lymphatic system in dental tissues. However, the evaluation of the lymphatic system of the teeth is problematic because it is quite difficult to clearly distinguish lymphatic vessels from small blood vessels.Despite many studies, opinions on the lymphatic system of the teeth are still incompatible. Studies using light and electron microscopy and directly using methods such as a radioisotope (radionuclide) scan and interstitial fluid pressure measurement reported incomplete results. Immunohistochemistry (IHC) plays the main role in investigating presence of the lymphatic system in dental tissues. This method uses labeled antibodies against antigens typical of lymphatic vessels. The use of appropriate staining enables the detection of antigen-antibody reaction products using a light (optical), electron or fluorescence microscope. However, these studies do not show the system of vessels, their histologic structure under physiological conditions and inflammation as well as the lymphangiogenesis process in the dental pulp. Unfortunately, there is a lack of studies associating the presence of lymphatic vessels in the dental pulp with local lymphatic nodes or large vessels outside the tooth. In the scientific and research environment, the evaluation of the lymphatic system of the teeth is problematic because it is quite difficult to clearly distinguish lymphatic vessels from small blood vessels. Despite many indications of the presence of lymphatic vessels in the pulp chamber, this problem remains open and needs further research.

Tumor Solid Stress: Assessment with MR Elastography under Compression of Patient-Derived Hepatocellular Carcinomas and Cholangiocarcinomas Xenografted in Mice.

Simple SummaryTumor biomechanical properties, including high viscoelasticity and tumor pressure (solid stress and interstitial fluid pressure), are linked to tumor severity. While tumor viscoelasticity can be quantified with MR elastography, a non-invasive method to quantify tumor pressure remains elusive. In patient-derived hepatocellular carcinomas and cholangiocarcinomas xenografted in mice, we observed that basal elasticity determined during MR elastography under compression had high diagnostic performance in assessing tumor fibrosis content and was independently influenced by interstitial fluid pressure. In contrast, compression stiffening rate had high diagnostic performance in assessing solid stress. Assessment of compression stiffening with MR elastography may provide a non-invasive biomarker of tumor solid stress.Malignant tumors have abnormal biomechanical characteristics, including high viscoelasticity, solid stress, and interstitial fluid pressure. Magnetic resonance (MR) elastography is increasingly used to non-invasively assess tissue viscoelasticity. However, solid stress and interstitial fluid pressure measurements are performed with invasive methods. We studied the feasibility and potential role of MR elastography at basal state and under controlled compression in assessing altered biomechanical features of malignant liver tumors. MR elastography was performed in mice with patient-derived, subcutaneously xenografted hepatocellular carcinomas or cholangiocarcinomas to measure the basal viscoelasticity and the compression stiffening rate, which corresponds to the slope of elasticity versus applied compression. MR elastography measurements were correlated with invasive pressure measurements and digital histological readings. Significant differences in MR elastography parameters, pressure, and histological measurements were observed between tumor models. In multivariate analysis, collagen content and interstitial fluid pressure were determinants of basal viscoelasticity, whereas solid stress, in addition to collagen content, cellularity, and tumor type, was an independent determinant of compression stiffening rate. Compression stiffening rate had high AUC (0.87 ± 0.08) for determining elevated solid stress, whereas basal elasticity had high AUC for tumor collagen content (AUC: 0.86 ± 0.08). Our results suggest that MR elastography compression stiffening rate, in contrast to basal viscoelasticity, is a potential marker of solid stress in malignant liver tumors.

Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

Preclinical studies have suggested that interstitial fluid pressure (IFP) is uniformly elevated in the central region of tumors, whereas clinical studies have revealed that IFP may vary among different measurement sites in the tumor center. IFP measurements are technically difficult, and it has been claimed that the intratumor heterogeneity in IFP reported for human tumors is due to technical problems. The main purpose of this study was to determine conclusively whether IFP may be heterogeneously elevated in the central tumor region, and if so, to reveal possible mechanisms and possible consequences. Tumors of two xenograft models were included in the study: HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma. IFP was measured with Millar SPC 320 catheters in two positions in each tumor and related to tumor histology or the metastatic status of the host mouse. Some tumors of both models showed significant intratumor heterogeneity in IFP, and this heterogeneity was associated with a compartmentalized histological appearance (i.e., the tissue was divided into compartments separated by thick connective tissue bands) in HL-16 tumors and with a dense collagen-I-rich extracellular matrix in Panc-1 tumors, suggesting that these connective tissue structures prevented efficient interstitial convection. Furthermore, some tumors of both models developed lymph node metastases, and of the two IFP values measured in each tumor, only the higher value was significantly higher in metastatic than in non-metastatic tumors, suggesting that metastatic propensity was determined by the tumor region having the highest IFP.

Targeting and microenvironment-improving of phenylboronic acid-decorated soy protein nanoparticles with different sizes to tumor.

It is essential for nanoparticles to delivery drugs accurately and penetrate deeply to tumor. However, complicated tumor microenvironment such as elevated tumor interstitial fluid pressure (IFP) and solid stress reduces the transport efficiency of nanomedicines in tumor.Methods: We herein report a drug delivery system of phenylboronic acid-decorated soy protein nanoparticles with the size of 30 nm, 50 nm and 150 nm. In vitro examinations including cytotoxicity, cellular uptake and penetration in multicellular tumor spheroids and in vivo observations including IFP and tumor solid stress measurements and antitumor activity were performed.Results: It was found that phenylboronic acid moiety could endow the nanoparticles actively targeting affinity to sialic acid (SA) which overexpressed in tumor cells. Simultaneously soy protein could improve tumor microenvironment such as reduction of IFP and tumor stress. Among the soy protein nanoparticles with different sizes, 30 nm-sized nanoparticles showed the best cellular uptake and highest cytotoxicity in vitro after loading doxorubicin (DOX). In vivo, 30 nm-sized nanoparticles showed the best tumor microenvironment improvement efficiency, leading to the enhanced drug accumulation and antitumor efficiency when combination with DOX.Conclusion: Our study introduces a bioactive nanoparticulate design strategy to actively target and significantly improve tumor microenvironment for enhanced cancer therapy.

Investigating Low-Velocity Fluid Flow in Tumors with Convection-MRI.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859-72. ©2018 AACR.

Abstract 2710: Model evolution technique as a novel concept for characterization of tumor heterogeneity in dynamic contrast enhanced MRI studies

Abstract Introduction: Many studies have shown that tumor vascular network and the assortment of tumorous cells inside and on the periphery of solid tumors are spatially heterogeneous. Variation in cell packing density (VCPD), hypoxia, acidosis, and elevated interstitial fluid pressure (IFP) are main characteristic features of solid tumors. Elevated IFP and VCPD in solid tumors can be generally relevant to the pathological structures at the cellular level that is fundamental to understanding the chance of response to treatment and recurrence. Therefore, non-invasive quantification of tumor heterogeneity for the same types of tumors can play an important role in diagnosis and treatment planning. Hypothesis: In this pilot study, using Nested Model (NM) selection technique, Model Evolution (ME) concept is framed and introduced to quantify the evolutions of 3 different physiologically NM that are derived from standard Tofts model, throughout the course of Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) experiment. Using ME technique for pharmacokinetic (PK) modeling and DCE-MRI data analysis, a heterogeneity measure is formulated and introduced based on the evolutionary profile of the estimated extra-cellular extra-vascular (ve) volume. We hypothesized that the ME profiles in the course of DCE-MRI experiment, highly depend on the inward diffusion and outward convection of contrast agent concentration and contain abundant information for describing the compartmentalization and heterogeneity levels of solid tumors. Material and Methods: 24 athymic Nude rats with U251n rat tumor model of cerebral tumor were studied. Look-Locker T1 mapping and DCE-MRI experiments (Dual Gradient Echo, 150 image sets at 4.0 sec intervals over 10 min: matrix = 128×64, five 2.0 mm slices, NE = 2, NA = 1, TE/TE/TR = 2.0/4.0/40ms with bolus intravenous injection of the Magnevist at 0.25 mmol/kg) acquired at 7T field strengths. In each animal, in-vivo measurement of tumor IFP was done right after the DCE-MRI experiment using a wick-in-needle technique. The ME technique was applied on DCE-MR data of 24 U251n rat tumors to characterize the heterogeneity of each tumor and then the results were compared to their known in vivo measure of IFPs. Results and Conclusions: Results of this pilot study clearly attest that the evolutionary profile of ve can be used to characterize the heterogeneity level of solid tumors. The ME results imply that as the slop of the evolutionary profile increases, the IFP of tumor increases. Also, the latency of the profile during the course of MR experiment can reliably explain the tumor compartmentalization and their elevated IFP. This pilot study confirms that the ME concept can make a paradigm shift in non-invasive quantification of tumor heterogeneity from DCE-MRI studies Citation Format: Hassan Bagher-Ebadian, Azimeh NV Dehkordi, Rasha Alamgharibi, David Nathanson, Hamid Soltanian-Zadeh, Arbab S. Ali, Stephen Brown, Meser M. Ali, Tom Mikkelsen, James R. Ewing. Model evolution technique as a novel concept for characterization of tumor heterogeneity in dynamic contrast enhanced MRI studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2710.

Dynamics of Interstitial Fluid Pressure in Extracellular Matrix Hydrogels in Microfluidic Devices.

In order to understand how interstitial fluid pressure and flow affect cell behavior, many studies use microfluidic approaches to apply externally controlled pressures to the boundary of a cell-containing gel. It is generally assumed that the resulting interstitial pressure distribution quickly reaches a steady-state, but this assumption has not been rigorously tested. Here, we demonstrate experimentally and computationally that the interstitial fluid pressure within an extracellular matrix gel in a microfluidic device can, in some cases, react with a long time delay to external loading. Remarkably, the source of this delay is the slight (∼100 nm in the cases examined here) distension of the walls of the device under pressure. Finite-element models show that the dynamics of interstitial pressure can be described as an instantaneous jump, followed by axial and transverse diffusion, until the steady pressure distribution is reached. The dynamics follow scaling laws that enable estimation of a gel's poroelastic constants from time-resolved measurements of interstitial fluid pressure.

Abstract P6-11-05: Tumor priming with cyclophosphamide for enhanced tumor delivery, penetration and anti-tumor activity of MM-302, HER2-targeted liposomal doxorubicin

Abstract MM-302, HER2-targeted PEGylated liposomal doxorubicin, is a liposomal antibody drug conjugate designed to target doxorubicin to HER2-overexpressing cancer cells, while limiting uptake into non-target cells. Effective tumor delivery and penetration are critical barriers to the clinical activity of nanomedicines, including liposomes. Cyclophosphamide has been successfully combined with both doxorubicin and liposomal doxorubicin in breast cancer therapy, with the two drugs being administered on the same day to patients. We have evaluated a novel sequential combination regimen of cyclophosphamide with MM-302 with the goal of improving tumor delivery and penetration of MM-302. Methods: Biodistribution studies were carried out in multiple tumor xenograft models to assess the delivery of MM-302 and free doxorubicin, either as single agents or in combination with cyclophosphamide at different dosing schedules. The total doxorubicin within tumors was quantified by HPLC and microscopically by determining the number of doxorubicin-positive nuclei within frozen tumor sections. Induction of DNA damage/repair, tumor cell apoptosis, and changes in the tumor architecture in response to drug treatment (tumor cell density and vascular parameters) were quantified by automated image analysis. Interstitial fluid pressure measurements were carried out to evaluate changes in the tumor physiology upon cyclophosphamide treatment. Anti-tumor activity studies in BT474-M3 tumor-bearing mice were performed to evaluate the ability of the different dosing regimens to inhibit tumor growth. Results: Pre-dosing of tumors with cyclophosphamide enhanced subsequent MM-302 delivery to tumor xenografts (2-3-fold) without affecting delivery to non-target tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Analysis of cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure and increase in vascular perfusion. Finally, treatment of tumors xenografts with cyclophosphamide followed by MM-302 resulted in a significantly greater tumor growth inhibition compared to either single agent alone. Conclusions: Rational combination of MM-302 with cyclophosphamide results in an active and tolerable regimen in preclinical models that enhances the tumor delivery and activity of MM-302, without affecting doxorubicin exposure to non-target organs. This novel sequential dosing strategy represents an advance in addressing the critical challenge for tumor delivery of nanomedicines. This work provided data supporting the initiation of a clinical evaluation of the effect of cyclophosphamide on MM-302 delivery as part of an on-going Phase 1 clinical trial of MM-302 in HER2-positive metastatic breast cancer (http://clinicaltrials.gov/show/NCT01304797). Citation Format: Elena Geretti, Shannon C Leonard, Nancy Dumont, Christopher W Espelin, Daniel F Gaddy, Thomas J Wickham, Bart S Hendriks. Tumor priming with cyclophosphamide for enhanced tumor delivery, penetration and anti-tumor activity of MM-302, HER2-targeted liposomal doxorubicin [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-05.

3E05 MEMSセンサを用いた固液二相性潤滑の流体圧力と摩擦力の同時直接測定(GS14:バイオトライボロジー)

3E05 MEMSセンサを用いた固液二相性潤滑の流体圧力と摩擦力の同時直接測定(GS14:バイオトライボロジー)

Assessment of the interstitial fluid pressure of tumors by dynamic contrast-enhanced magnetic resonance imaging with contrast agents of different molecular weights

Background. Cancer patients showing highly elevated interstitial fluid pressure (IFP) in the primary tumor may benefit from particularly aggressive treatment. There is some evidence that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful non-invasive method for providing information on the IFP of tumors. The purpose of this preclinical study was to investigate whether any association between DCE-MRI-derived parametric images and tumor IFP can be strengthened by using MR contrast agents with higher molecular weights than that of Gd-DTPA. Material and methods. A-07 human melanoma xenografts were used as preclinical models of human cancer. Three contrast agents were compared: Gd-DTPA (0.55 kDa), P846 (3.5 kDa), and gadomelitol (6.5 kDa). A total of 46 tumors were subjected to DCE-MRI and subsequent measurement of IFP. Parametric images of Ktrans (the volume transfer constant of the contrast agent) and ve (the fractional distribution volume of the contrast agent) were produced by pharmacokinetic analysis of the DCE-MRI series. Results. Significant inverse correlations were found between median Ktrans and IFP for Gd-DTPA (p = 0.0076; R2 = 0.46; n = 14) and P846 (p = 0.0042; R2 = 0.45; n = 16), whereas there was no correlation between median Ktrans and IFP for gadomelitol (p > 0.05; n = 16). Significant correlation between median ve and IFP was not found for any of the contrast agents (p > 0.05 for Gd-DTPA, P846, and gadomelitol). Conclusion. Ktrans images, but not ve images, derived by pharmacokinetic analysis of DCE-MRI data for low-molecular-weight contrast agents may provide information on the IFP of tumors. Any association between Ktrans and IFP cannot be expected to be improved by using contrast agents with higher molecular weights than those of Gd-DTPA and P846.

Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model.

Interstitial fluid pressure correlates with intravoxel incoherent motion imaging metrics in a mouse mammary carcinoma model

The effective delivery of a therapeutic drug to the core of a tumor is often impeded by physiological barriers, such as the interstitial fluid pressure (IFP). There are a number of therapies that can decrease IFP and induce tumor vascular normalization. However, a lack of a noninvasive means to measure IFP hinders the utilization of such a window of opportunity for the maximization of the treatment response. Thus, the purpose of this study was to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion parameters as noninvasive imaging biomarkers for IFP. Mice bearing the 4T1 mammary carcinoma model were studied using diffusion-weighted imaging (DWI), immediately followed by wick-in-needle IFP measurement. Voxelwise analysis was conducted with a conventional monoexponential diffusion model, as well as a biexponential model taking IVIM into account. There was no significant correlation of IFP with either the median apparent diffusion coefficient from the monoexponential model (r = 0.11, p = 0.78) or the median tissue diffusivity from the biexponential model (r = 0.30, p = 0.44). However, IFP was correlated with the median pseudo-diffusivity (D(p)) of apparent vascular voxels (r = 0.76, p = 0.02) and with the median product of the perfusion fraction and pseudo-diffusivity (f(p)D(p)) of apparent vascular voxels (r = 0.77, p = 0.02). Although the effect of IVIM in tumors has been reported previously, to our knowledge, this study represents the first direct comparison of IVIM metrics with IFP, with the results supporting the feasibility of the use of IVIM DWI metrics as noninvasive biomarkers for tumor IFP.

Assessment of tumor hypoxia and interstitial fluid pressure by gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging

Background and purposeExtensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor may cause resistance to radiation treatment and promote metastatic spread. The potential of gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the extent of hypoxia and the level of interstitial hypertension in tumors was investigated in this preclinical study. Materials and methodsTwenty-three A-07 tumors were subjected to DCE-MRI and subsequent measurement of IFP and fraction of pimonidazole-positive hypoxic tissue (HFPim). Parametric tumor images of Ktrans, ve, and VbTofts (Tofts model) and of Ki and VbPatlak (Patlak model) were produced by pharmacokinetic analyses of the DCE-MRI series. ResultsThere was no correlation between IFP and HFPim in the tumors. Ktrans and Ki decreased significantly with increasing HFPim, whereas VbTofts and VbPatlak increased significantly with increasing IFP. ConclusionInformation on both the extent of hypoxia and the level of interstitial hypertension in A-07 tumors can be derived from a single DCE-MRI series by using gadomelitol as contrast agent.

A batch fabricated capacitive pressure sensor with an integrated Guyton capsule for interstitial fluid pressure measurement

In this paper, we present the design, fabrication and test of a batch fabricated capacitive pressure sensor with an integrated Guyton capsule for interstitial fluid pressure measurement. The sensor is composed of 12 µm thick single crystalline silicon membrane and a 3 µm gap, hermetically sealed through silicon–glass anodic bonding. A novel batch scale method for creating electrical feed-throughs inside the sealed capacitor chamber is developed. The Guyton capsule consists of an array of 10 µm diameter access holes etched onto a silicon back-plate separated from the silicon sensing membrane by a gap of 5 µm. The presence of the Guyton capsule (i.e. plates with access holes plus the gap separating them from the sensing membrane) allows for the ingress of interstitial fluid inside the 5 µm gap following the implantation, thus, providing an accurate measurement of interstitial fluid pressure. The fabricated sensor is 3 × 2 × 0.42 mm3 in dimensions and has a maximum sensitivity of 10 fF mmHg−1.

Measurement of interstitial fluid pressure (IFP) and circulating biomarkers in soft tissue sarcoma (STS): An exploratory phase II clinical and correlative study of sorafenib (SOR) in patients with refractory STS (NCI Protocol 6948).

10091 Background: Interstitial hypertension may contribute to chemo-resistance in STS. Sorafenib is a small molecule tyrosine kinase inhibitor with potent activity against c-RAF/B-RAF, VEGFR-2, and PDGFR-β. By affecting vascular permeability, SOR may potentially reduce IFP. We assessed anti-tumor activity and measured the IFP and circulating biomarkers in patients with superficial refractory STS treated with SOR. Methods: Eligibility criteria included advanced/metastatic STS with no known curative therapy, measurable disease with at least one superficial lesion (>1cm) amenable to biopsy, age ≥18, ECOG performance status ≤2, and no prior SOR therapy. SOR was administered at 400mg BID. IFP measurements were performed intraoperatively as described (Boucher et al 1991); plasma biomarkers were collected pre- and on Day 28 post-SOR. Results: Fifteen patients (median age 59, range 30-84) were enrolled, 14 of whom had prior chemotherapy and/or radiation. Median tumor size was 6.6cm (range 1.3-10.7cm). Common sarcoma sub-types included leiomyosarcoma (27%), myxofibrosarcoma (13%) and synovial sarcoma (13%). Of these, 11 had superficial tumor amenable to biopsy. In this group, median TTP was 28 days (range 10-81). In four pts lacking palpable superficial tumor, mean TTP was 173 days (range 28-227). Best response was stable disease in 10 of 15 pts, maintained for a median 57 days (range 20-168 days). IFP measurements were obtained in 6 pts at baseline and showed a direct correlation with tumor size (Kendall's tau=0.87, p=0.017). Two pts with SD had corresponding post-SOR IFP evaluation and demonstrated a decline in IFP. SOR significantly increased plasma VEGF, PlGF and SDF-1a and decreased sVEGFR2 (p<0.05 for all). Conclusions: SOR has modest benefits in this population, most of whom had advanced refractory disease. IFP appears to decrease when response is maintained. Biomarker changes were consistent with inhibition of angiogenesis by SOR. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, ARIAD, ArQule, AstraZeneca, Bayer, Daiichi Sankyo, Dyax, Genentech, Infinity, Johnson & Johnson, Millennium, Novartis, Pfizer, PharmaMar, Regeneron, Roche, SynDevRx, ZIOPHARM Oncology SynDevRx Novartis, Pfizer, PharmaMar Amgen, ARIAD, ArQule, Daiichi Sankyo, Genentech, Infinity, Johnson & Johnson, Novartis, Pfizer, PharmaMar, Roche, ZIOPHARM Oncology ARIAD, ArQule, Daiichi Sankyo, Infinity, Johnson & Johnson, PharmaMar

Abstract 4472: NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: Comparison with NVP-BEZ235

Abstract Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition. For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments. BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease. In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4472.

Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation Therapy

To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy. Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre-radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid-radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival. Median pre-radiation therapy and mid-radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, -1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre-radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reduction of interstitial fluid pressure was noted only in patients with complete responses (P = 0.002), and mid-radiation therapy interstitial fluid pressure was significantly lower in patients with complete responses (P = 0.036). In the multivariate analysis including interstitial fluid pressures and clinical variables, pre-radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively). Mid-radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre-radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy.

Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure

Background and purpose High interstitial fluid pressure (IFP) in the primary tumor has been shown to promote metastasis in melanoma xenografts and to predict for poor survival in cervical cancer patients. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing tumor IFP noninvasively was investigated in the present study. Materials and methods A-07 and R-18 melanoma xenografts with and without necrotic regions were subjected to DCE-MRI and subsequent measurement of IFP. Tumor images of E· F ( E is the initial extraction fraction of Gd-DTPA and F is blood perfusion) and λ ( λ is proportional to extracellular volume fraction) were produced by Kety analysis of DCE-MRI series. Results In tumors without necrosis, significant inverse correlations were found between E· F and IFP, both for A-07 and R-18 tumors, and between λ and IFP for A-07 tumors. Significant correlations beween E· F and IFP or between λ and IFP could not be detected for tumors with necrotic regions. Conclusions DCE-MRI may be developed to be a useful noninvasive method for assessing IFP in tumors without necrosis. This possibility warrants further studies involving several physiologically different experimental tumor lines, as well as human tumors.

Measuring interstitial fluid pressure with fiberoptic pressure transducers

In this report we describe a practical procedure for measuring interstitial fluid pressure (IFP) using fiberoptic pressure transducers based on optical interferometry. Eight mice were used for subcutaneous IFP measurements and four mice for intramuscular IFP measurements with a FOBPS-18 fiberoptic pressure transducer. We used four mice for subcutaneous IFP measurements with a SAMBA-420 MR fiberoptic pressure transducer. One measurement was made for each mouse simultaneously by using a fiberoptic system and an established approach, either transducer-tipped catheter or wick-in-needle technique. The mean IFP values obtained in subcutaneous tissues were − 3.00 mm Hg (SEM −/+ 0.462, n = 8), − 3.25 mm Hg (SEM −/+ 0.478, n = 4), − 3.34 mm Hg (SEM −/+ 0.312, n = 6), and − 2.85 (SEM −/+ 0.57, n = 6) for the FOBPS fiberoptic transducer, the SAMBA fiberoptic transducer, the transducer-tipped catheter, and the wick-in-needle technique, respectively. There was no difference between these techniques to measure IFP (Friedman test, p = 0.7997). The subcutaneous IFP measurements showed strong linear correlation between fiberoptic transducer and transducer-tipped catheter ( R 2 = 0.9950) and fiberoptic transducer and wick-in-needle technique ( R 2 = 0.9966). Fiberoptic pressure transducers measure the interstitial fluid pressure accurately, comparable to conventional techniques. The simplified IFP measurement procedures described in this report will allow investigators to easily measure IFP, and elucidate the unit pressure change per unit volume change (d P/d V) in normal or cancer tissues in the presence of strong electromagnetic fields encountered in MRI.