Interstitial Fluid Pressure Values Research Articles

Longitudinal Monitoring of Simulated Interstitial Fluid Pressure for Pancreatic Ductal Adenocarcinoma Patients Treated with Stereotactic Body Radiotherapy.

Simple SummaryHigh vessel permeability, poor perfusion, low lymphatic drainage, and dense abundant stroma elevate interstitial fluid pressures (IFP) in pancreatic ductal adenocarcinoma (PDAC). The present study aims to monitor longitudinal changes in simulated tumor IFP and velocity (IFV) values using a dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) approach in PDAC. Nine PDAC patients underwent DCE-MRI acquisition on a 3-Tesla MRI scanner at pre-treatment (TX (0)), immediately after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation using the Starling Principle of fluid exchange and Darcy velocity–pressure relationship was solved in COMSOL Multiphysics software to generate IFP and IFV parametric maps using relevant tumor tissue physiological parameters. Initial results suggest that after validation, IFP and IFV can be imaging biomarkers of early response to therapy that may guide precision medicine in PDAC.The present study aims to monitor longitudinal changes in simulated tumor interstitial fluid pressure (IFP) and velocity (IFV) values using dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) in pancreatic ductal adenocarcinoma (PDAC) patients. Nine PDAC patients underwent MRI, including DCE-MRI, on a 3-Tesla MRI scanner at pre-treatment (TX (0)), after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation, incorporating the Starling Principle of fluid exchange, Darcy velocity, and volume transfer constant (Ktrans), was solved in COMSOL Multiphysics software to generate IFP and IFV maps. Tumor volume (Vt), Ktrans, IFP, and IFV values were compared (Wilcoxon and Spearman) between the time- points. D2-TX Ktrans values were significantly different from pre-TX and D1-TX (p < 0.05). The D1-TX and pre-TX mean IFV values exhibited a borderline significant difference (p = 0.08). The IFP values varying <3.0% between the three time-points were not significantly different (p > 0.05). Vt and IFP values were strongly positively correlated at pre-TX (ρ = 0.90, p = 0.005), while IFV exhibited a strong negative correlation at D1-TX (ρ = −0.74, p = 0.045). Vt, Ktrans, IFP, and IFV hold promise as imaging biomarkers of early response to therapy in PDAC.

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.

Mechanistic evaluation of the combination effect of paclitaxel (Pac) and bevacizumab (Bev) in breast cancer xenografts

11007 Background: Chemosensitization is the ability to augment the effects of standard chemotherapy. One of the possible mechanisms for chemosensitization is improving intratumoral chemotherapy concentrations by increasing total or regional delivery of chemotherapy to the tumor. This mechanism potentially leads to a decreased tumor interstitial fluid pressure (IFP). This study evaluates the interaction between tumor IFP, intra-tumor drug accumulation and blood vessel perfusion. Methods: GILM2 human breast cancer (triple negative phenotype) cells were injected into the mammary fat pad of female nude mice. Mice were randomized to 4 arms: Control, Pac 24 mg/Kg, Bev 10 mg/Kg, and the same dose for the combination Pac + Bev, twice a week for 3 weeks. Tumor IFP was assessed using an ultraminiature catheter-tip technique (Ozerdem 2005). Concentration of Pac in tumor tissue was measured using liquid chromatography mass spectrometry (LC/MS) and blood vessel perfusion was assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Ultrastructural morphology changes were assessed by electron microscopy (EM). Results: Treatment started 35 days after implantation; tumor tissue concentration of Pac was significantly increased when combined with Bev (P = 0.03). In mice treated with the combination of Pac + Bev, IFP values decreased more gradually, with sustained and significant reduction at the end of the treatment (P = 0.0068; mean SEM day 0: 28,44 ± 6,1; mean SEM day 21: 7,41 ± 2,0). The IFP changes in the other 3 experimental arms did not reach statistical significance. The combination of Pac and Bev produced substantial changes to the proportions of endothelial cell/pericytes and increased apoptosis in tumor cells by 75% (detected by immunostaining for cleaved-caspase 3). Conclusions: The combination of Pac and Bev produces significant tumor reduction and increases three-fold the concentration of Pac in the tumor. This intra-tumor augmentation of Pac was correlated with the decrease of tumor IFP, which was independent of the action of Bev alone. Results of DCE-MRI and EM analyses of the treated tumors will also be presented. No significant financial relationships to disclose.

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.

High interstitial fluid pressure in rat tongue cancer is related to increased lymph vessel area, tumor size, invasiveness and decreased body weight

Interstitial fluid pressure (IFP) in most tumors is high, and this high pressure has been correlated with poor prognosis. Measurements of IFP in normal tongue and in tongue cancer are lacking. Recent research suggests the existence of a relationship between increased peritumoral lymph vessels (PTLV) and survival, and a correlation of increased lymphatic vessel density with an unfavorable prognosis has been reported. In the present study, tongue squamous cell carcinoma (SCC) was induced by adding the carcinogen 4-nitroquinoline oxide in drinking water for 19 weeks. The IFP was measured by micropuncture and immunohistochemistry was used to visualize lymph vessels. In normal tongue, IFP averaged 3.1 +/- 0.3 mmHg. The IFP, both in the tumor (29.1 +/- 2.9 mmHg) and 0.5 cm anterior to it (15.4 +/- 2.1 mmHg) was consistently increased (P < 0.005) with values ranging from 10 to 40 mmHg. The highest IFP values were measured in rats with large tumors (P < 0.05) and low body weight (P < 0.001), suggesting that IFP increases with cancer progression. Lymphatic vessel area (%), as determined with the lymphatic specific marker LYVE-1 antibody, was significantly increased in the peritumoral area when compared to intratumoral and control mucosa (P < 0.05). There was a significant positive correlation between IFP, PTLV area, tumor size and invasiveness. Our data show that IFP is increased in tongue cancer. Corresponding changes in PTLV area, invasiveness, tumor area and IFP suggest that the increased pressure is caused by defective lymph drainage and solid stress generated by tumor cells growing in a low compliant environment.

Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

BackgroundHigh tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.MethodsKHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging.ResultsTumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown i/m versus orthotopically despite differences in IFP.ConclusionOur studies across a range of different tumour models showed substantial heterogeneity in tumour IFP, suggesting differences in the vascular development and interstitial fluid dynamics in the individual tumours. The results demonstrate a strong stochastic aspect to tumour IFP development, notably the variation apparent between different tumours within the same animal and the lack of correlation between donor and recipient tumours.

Cell Proliferation of Cultured Human Cancer Cells are Affected by the Elevated Tumor Pressures that Exist In Vivo

Elevated interstitial fluid pressure (IFP) is observed in most solid tumors. However, the study of the cellular processes of tumors and the development of chemotherapy are routinely studied using in vitro culture systems at atmospheric pressure. Using a new pressurized cell culture system, we investigated the influence of hydrostatic pressure on population dynamics of three primary osteosarcoma (HOS, U2OS, SaOS2) and two metastatic tumor cell lines (MCF7 breast, H1299 lung) that invade bone. Values of IFP in normal human bone and muscle, and in osteosarcoma tumors obtained during their surgical biopsy established the hydrostatic pressure range for the in vitro cell studies. The IFP values were obtained from a retrospective review of patient records. IFP from confirmed osteosarcoma was 35.9+/- 16.2 mmHg. Tumor IFP was significantly higher than muscle IFP (p < 0.001) and bone IFP (p < 0.003). The in vitro study measured the cell-line proliferation using hydrostatic pressures of 0, 20, 50 and 100 mmHg. The findings suggest that hydrostatic pressure either increases or decreases tumor proliferation rates depending on cell type. Furthermore, cell death was not associated with apoptosis.

Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements

Interstitial fluid pressure (IFP) and oxygen (pO(2)) measurements are prognostic factors in cervical cancer. The purpose of this study was to determine the relationship between IFP and oxygenation and parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT). Dynamic contrast-enhanced computed tomography was performed in 32 patients with cervical cancer before radiation therapy. Images were acquired during intravenous contrast injection at 1 per s for 120 s and 1 per 15 s for 60 s. DCE-CT was analyzed using CT Perfusion 3 software (GE Medical Systems) to derive tumor blood flow (BF), permeability surface area product, blood volume, and mean transit time. Further analysis was performed to obtain relative peak enhancement, residual enhancement at 3 min after contrast injection (RE), time to peak and initial slope. Nodal status and tumor size were assessed with MRI. From in vivo IFP (n = 31) and pO(2) (n = 31) tumor measurements median pO(2) (mO(2)), percentage measurements less than 5 mm Hg (HP5) and mean IFP values were calculated. There was a positive correlation between BF and mO(2) (r = 0.47, p = 0.007) and between RE and HP5 (r = 0.39, p = 0.03). There was no correlation between IFP and DCE-CT parameters. There is a moderately positive, correlation between tumor oxygenation and BF as well as RE and HP5. Further study is required to determine if DCE-CT parameters are useful predictors of tumor behavior in cervical cancer.

Radiobiological hypoxia, oxygen tension, interstitial fluid pressure and relative viable tumour area in two human squamous cell carcinomas in nude mice during fractionated radiotherapy.

Very little is known about the correlation between the radiobiological hypoxic fraction (rHF) and other measures of tumour oxygenation during fractionated irradiation. In the present study the rHF is determined in untreated human FaDu and GL squamous cell carcinoma in nude mice and in tumours irradiated with 10 fractions in 2 weeks and 20 fractions in 4 weeks, using tumour control as the experimental endpoint. The results were compared with measurements of the pO2, the interstitial fluid pressure (IFP) and the relative viable tumour area. In FaDu tumours the radiobiological hypoxic fractions (rHFs) before and during irradiation were not statistically different from 100%. Depending on the assumptions made for D0, the rHFs of GL tumours were between 0.2 and 4% or 30 and 53%. The median pO2 values were 2.8 mmHg for untreated FaDu tumours and 0.2 mmHg for GL tumours (p < 0.001). The median IFP values were 2.6 mmHg in FaDu and 5.3 mmHg in GL tumours (p = 0.01). No important changes in the pO2 and IFP values were observed during fractionated irradiation. The relative viable tumour area during irradiation decreased by 83% in FaDu tumours (p = 0.002) and by 54% in GL tumours (p = 0.003). It is concluded that differences in rHF exist between FaDu and GL tumours before and during fractionated irradiation and that these differences are not reflected by pO2 and IFP values and the relative viable tumour area.

Radiobiological Hypoxia, Oxygen Tension, Interstitial Fluid Pressure and Relative Viable Tumour Area in Two Human Squamous Cell Carcinomas in Nude Mice During Fractionated Radiotherapy

Very little is known about the correlation between the radiobiological hypoxic fraction (rHF) and other measures of tumour oxygenation during fractionated irradiation. In the present study the rHF is determined in untreated human FaDu and GL squamous cell carcinoma in nude mice and in tumours irradiated with 10 fractions in 2 weeks and 20 fractions in 4 weeks, using tumour control as the experimental endpoint. The results were compared with measurements of the pO2, the interstitial fluid pressure (IFP) and the relative viable tumour area. In FaDu tumours the radiobiological hypoxic fractions (rHFs) before and during irradiation were not statistically different from 100%. Depending on the assumptions made for D0, the rHFs of GL tumours were between 0.2 and 4% or 30 and 53%. The median pO2 values were 2.8 mmHg for untreated FaDu tumours and 0.2 mmHg for GL tumours (p < 0.001). The median IFP values were 2.6 mmHg in FaDu and 5.3 mmHg in GL tumours (p = 0.01). No important changes in the pO2 and IFP values were observed during fractionated irradiation. The relative viable tumour area during irradiation decreased by 83% in FaDu tumours (p = 0.002) and by 54% in GL tumours (p = 0.003). It is concluded that differences in rHF exist between FaDu and GL tumours before and during fractionated irradiation and that these differences are not reflected by pO2 and IFP values and the relative viable tumour area.