Eribulin induces tumor vascular remodeling through intussusceptive angiogenesis in a sarcoma xenograft model.

Eribulin is a novel microtubule inhibitor that, similar to other types of microtubule inhibitors, induces apoptosis by inhibiting the mitotic division of cells. Besides this direct effect on tumor cells, previous studies have shown that eribulin has the potential to induce tumor vascular remodeling in several different cancers; however, the mechanisms underlying this phenomenon remain unclear. In the present study, we aimed to elucidate whether eribulin is effective against synovial sarcoma, a relatively rare sarcoma that often affects adolescents and young adults, and to histologically investigate the microstructure of tumor vessels after the administration of eribulin. We found that eribulin exhibits potent antitumor activity against synovial sarcoma in a tumor xenograft model and that tumor vessels frequently have intervascular pillars, a hallmark of intussusceptive angiogenesis (IA), after the administration of eribulin. IA is a distinct form of angiogenesis that is involved in normal developmental processes as well as pathological conditions. Our data indicate that IA is potentially involved in eribulin-induced vascular remodeling and thereby suggest previously unacknowledged role of IA in regulating the tumor vasculature after eribulin administration.

Laser speckle contrast analysis (LASCA) technology for the semiquantitative measurement of angiogenesis in in-ovo-tumor-model.

BACKGROUND: The process of angiogenesis is a key element for tumor growth and proliferation and therefore one of the determining factors for aggressiveness and malignancy. A better understanding of the underlying processes of tumor induced angiogenesis is crucial for superior cancer treatment. Furthermore, the PeriCam perfusion speckle imager (PSI) system high resolution (HR) model by PERIMED presents a noninvasive method for semi-quantitative measurement of blood perfusion, based on laser speckle contrast analysis (LASCA). Aim of the present study was to utilize the chick chorioallantoic membrane (CAM) model as an in-ovo-tumor-model which enables rapid neovascularization of tumors while allowing real-time observation of the microcirculation via LASCA. METHODS: Fertilized chicken eggs were grafted with embryonal/alveolar rhabdomyosarcoma cells or primary sarcoma tumors. The blood perfusion was measured before and after tumor growth using LASCA. The procedure is accelerated and simplified through the integrated PIMSoft software which provides real-time graphs and color-coded images during the measurement. RESULTS: Sarcoma cells and primary sarcoma tumors exhibited satisfactory growth processes on the CAM. LASCA visualized microcirculation accurately and enabled an extensive investigation of the angiogenic potential of sarcoma cells on the CAM. We were able to show that sarcoma cells and primary sarcoma tumors induced larger quantities of neovasculature on the CAM than the controls. CONCLUSIONS: The utilization of LASCA for the investigation of tumor angiogenesis within the CAM model appears to be a highly beneficial, cost-efficient and easily practicable procedure. The proposed model can be used as a drug-screening model for individualized cancer therapy, especially with regards to anti-angiogenic agents.

Personalising sarcoma care using quantitative multimodality imaging for response assessment.

Over the last decades, technological developments in the field of radiology have resulted in a widespread use of imaging for personalising medicine in oncology, including patients with a sarcoma. New scanner hardware, imaging protocols, image reconstruction algorithms, radiotracers, and contrast media, enabled the assessment of the physical and biological properties of tumours associated with response to treatment. In this context, medical imaging has the potential to select sarcoma patients who do not benefit from (neo-)adjuvant treatment and facilitate treatment adaptation. Due to the biological heterogeneity in sarcomas, the challenge at hand is to acquire a practicable set of imaging features for specific sarcoma subtypes, allowing response assessment. This review provides a comprehensive overview of available clinical data on imaging-based response monitoring in sarcoma patients and future research directions. Eventually, it is expected that imaging-based response monitoring will help to achieve successful modification of (neo)adjuvant treatments and improve clinical care for these patients.

Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself.

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas. Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fortunately, preclinical studies and clinical trials have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Actually, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma.

BACKGROUND: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. METHODS: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. RESULTS: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50%. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. CONCLUSIONS: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.

Influence of temporal parameters of DCE-MRI on the quantification of heterogeneity in tumor vascularization.

BACKGROUND: Evaluating heterogeneity in tumor vascularization through texture analysis could improve predictions of patients' outcome and response evaluation. PURPOSE: To investigate the influence of temporal parameters on texture features extracted from dynamic contrast-enhanced (DCE)-MRI parametric maps. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Twenty-five adults with soft-tissue sarcoma (STS), median age: 68 years. FIELD STRENGTH/SEQUENCE: DCE-MRI acquisition using a CAIPIRINHA-Dixon-TWIST-VIBE sequence at 1.5T (temporal resolutions: 2 sec, duration: 5 min). ASSESSMENT: The area under time-intensity curve (AUC) and Ktrans maps were generated for several temporal resolution (dt = 2 sec, 4 sec, 6 sec, 8 sec, 10 sec, 12 sec, 20 sec) and scan durations (T = 3 min, 4 min, 5 min for a 6-sec sampling) by downsampling and truncating the initial DCE-MRI sequence. Tumor volume was manually segmented and propagated on all parametric maps. Thirty-two first- and second order-texture features were extracted per map to quantify the intratumoral heterogeneity. STATISTICAL TESTS: The influence of temporal parameters on texture features was studied with repeated-measures analysis of variance (or nonparametric equivalent). The dispersion of each texture feature depending on temporal parameters was estimated with coefficients of variation (CVs). The performances of multivariate models to predict the response to chemotherapy (ie, binary logistic regression based on the baseline texture features) were compared. RESULTS: The temporal resolution had a significant influence on 12/32 (37.5%) and 14/32 (43.8%) texture features evaluated on AUC and Ktrans maps, respectively (range of P < 0.0001-0.0395). Scan duration had a significant influence on 23/32 (71.9%) texture features from Ktrans map (range of P < 0.0001-0.0321). Dispersion was high (mean CV >0.5) with sampling for 2/32 (6.3%) and 10/32 (31.3%) features from AUC and Ktrans maps, respectively; and with truncating for 6/32 (18.8%) features from Ktrans map. The area under the receiver operating characteristics curve of predictive models ranged from 0.77 (95% confidence interval [CI] = [0.54-1.00], with dt = 6 sec T = 4 min) to 0.90 (95% CI = [0.74-1.00], with dt = 6 sec T = 5 min). DATA CONCLUSION: The values of texture features extracted from DCE-MRI parametric maps can be influenced by temporal parameters, which can lead to variations in performance of predictive models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1773-1788.

[A Case of Adult Undifferentiated Sarcoma of the Liver with Intraatrial Metastasis].

A 24-year-old woman was admitted to the hospital for abdominal pain. Abdominal contrast-enhanced computed tomography( CT)revealed a cystic mass measuring 11×8 cm in the left lobe of the liver with extravasation. Vascular embolization was performed, but extravasation remained on CT images. She was then transferred to our hospital. We performed an emergency extended left hepatectomy. Histopathological examination revealed solid proliferation of spindle-shaped cells. Immunohistochemical staining showed that the tumor cells were positive for vimentin and negative for AE1/AE3. Thus, a diagnosis of undifferentiated sarcoma was confirmed. Multiple recurrent tumors were recognized on CT images of the lung and right atrium taken 1 year and 10 months post-surgery. Partial resection of the tumor was performed for the right atrial mass, the left lingular segment, the left inferior lobe, and the right middle lobe. Pathological diagnosis confirmed metastasis of undifferentiated sarcoma from the liver. Chemotherapy consisting of vincristine, actinomycin D, and cyclophosphamide(VAC) was not effective, and the patient died 31 months after the primary surgery. Undifferentiated sarcoma of the liver is a rare malignant mesenchymal tumor, whose occurrence is extremely rare in adults. Although surgical treatment is the first choice, outcomes remain poor. Multimodality treatment should be used to improve the outcome.

Temporal changes in tumor oxygenation and perfusion upon normo- and hyperbaric inspiratory hyperoxia.

BACKGROUND: Inspiratory hyperoxia under hyperbaric conditions has been shown to effectively reduce tumor hypoxia and to improve radiosensitivity. However, applying irradiation (RT) under hyperbaric conditions is technically difficult in the clinical setting since RT after decompression may be effective only if tumor pO2 remains elevated for a certain period of time. The aim of the present study was to analyze the time course of tumor oxygenation and perfusion during and after hyperbaric hyperoxia. MATERIALS AND METHODS: Tumor oxygenation, red blood cell (RBC) flux for perfusion monitoring, and vascular resistance were assessed continuously in experimental rat DS-sarcomas by polarographic catheter electrodes and laser Doppler flowmetry at 1 and 2 atm (bar) of environmental pressure during breathing of pure O2 or carbogen (95 % O2 + 5 % CO2). RESULTS: During room air breathing, the tumor pO2 followed very rapidly within a few minutes the change of the ambient pressure during compression or decompression. With O2 breathing under hyperbaric conditions, the tumor pO2 increased more than expected based on the rise of the environmental pressure, although the time course was comparably rapid. Breathing carbogen, the tumor pO2 followed with a slight delay of the pressure change, and within 10 min after decompression the baseline values were reached again. RBC flux increased during carbogen breathing but remained almost constant with pure O2, indicating a vasodilation (decrease in vascular resistance) with carbogen but a vasoconstriction (increase in vascular resistance) with O2 during hyperbaric conditions. CONCLUSION: Since the tumor pO2 directly followed the environmental pressure, teletherapy after hyperbaric conditions does not seem to be promising as the pO2 reaches baseline values again within 5-10 min after decompression.

Targeted therapy in sarcomas other than GIST tumors.

Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials.

[COMBINATION OF VESSEL EMBOLIZATION AND CRYOTHERAPY IN SURGICAL TREATMENT OF SOFT TISSUE SARCOMAS].

The article analyzed the results of surgical treatment of 153 patients with soft tissue sarcomas. The surgery was complemented by preoperative embolization of vessels, which supplied the tumor, cryotherapy on the tumor and postoperative wound in 72 patients of main group. The control group consisted of 81 patients and there weren't any perioperative actions. It was shown, that more than 80% of soft tissue sarcomas had the main and mixed type of tumor blood supply. Partial and full reduction of blood flow could be obtained by embolization of the tumor in more than 50% patients. Combination of surgical and preoperative embolization of vessels and cryotherapy decreased the rate of local recurrence and increased the quantity of organosafe interventions.

Follicle-stimulating hormone receptor expression in soft tissue sarcomas.

AIMS: In adult humans, the follicle-stimulating hormone receptor (FSHR) is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. Recently, it has been shown that FSHR is expressed selectively on the surface of blood vessels in a wide range of tumours. So far, the expression of FSHR in mesenchymal tumours has not been studied. METHODS AND RESULTS: We performed a semiquantitative evaluation of FSHR protein expression in a large cohort of soft tissue sarcomas (STS; n = 335), including 11 subtypes. FSHR-positive vessels were detected in all sarcoma subtypes analysed. Among liposarcomas, significantly more cases of dedifferentiated liposarcomas (28 of 44) showed FSHR expression compared to well-differentiated liposarcomas (WDLS; four of 21; P < 0.001). Vessels in lipomas (n = 9) and non-neoplastic fat were FSHR-negative. FSHR expression was also detected in tumour cells of all sarcoma subtypes examined, with the lowest incidence in WDLS (three of 21; 14.3%) and the highest frequency in undifferentiated high-grade pleomorphic sarcomas (41 of 60; 68.3%). CONCLUSIONS: These data supplement the previously reported results of FSHR expression in endothelial cells of various cancer types and form a solid basis for further studies of FSHR in mesenchymal neoplasms.

Differential remodeling of cadherins and intermediate cytoskeletal filaments influence microenvironment of solid and ascitic sarcoma.

Different forms of sarcoma (solid or ascitic) often pose a critical medical situation for pediatric or adolescent group of patients. To date, predisposed genetic anomalies and related changes in protein expression are thought to be responsible for sarcoma development. However, in spite of genetic abnormality, role of tumor microenvironment is also indispensable for the evolving neoplasm. In our present study, we characterized the deferentially remodeled microenvironment in solid and ascitic tumors by sequential immunohistochemistry and flowcytometric analysis of E-cdaherin, N-cadherin, vimentin, and cytokeratin along with angiogenesis and metastasis. In addition, we considered flowcytometric apoptosis and CD133 positive cancer stem cell analysis. Comparative hemogram was also considered as a part. Our investigation revealed that both types of tumor promoted neovascularization over time with sign of local inflammation. Invasion of neighboring skeletal muscle by solid sarcoma was more frequent than its ascitic counterpart. In contrary, rapid and earlier cadherin switching (E-cadherin to N-cadherin) in ascitic sarcoma made them more aggressive than that of solid sarcoma and helped to early metastasize distant tissue like liver through the hematogenous route. Differential cadherin switching and infidelity of cytokeratin expression in Vimentin positive sarcoma also influenced the behavior of ascitic CD133+ cancer initiating cell pool with respect to CD133+ cells housed in solid sarcoma. Therefore our study concludes that differential cadherin switching program and infidelity of intermediate filaments in part, sharply discriminate the severity and metastatic potentiality of either type of sarcoma accompanying with CD133+ cellular repertoire. Besides, tumor phenotype-based dichotomous cadherin switching program could be exploited as a future drug target to manage decompensated malignant ascitic and solid sarcoma.

Endovascular palliation of multivessel blowout syndrome in the setting of a nonresectable neck sarcoma.

Carotid blowout syndrome is a rare life-threatening complication of head and neck malignancy. Current literature has focused exclusively on the carotid system and associated branches. We present a unique case of multivessel blowout in the setting of a large nonresectable neck sarcoma requiring various endovascular techniques for palliation.

Imaging features of primary sarcomas of the great vessels in CT, MRI and PET/CT: a single-center experience.

BACKGROUND: To investigate the imaging features of primary sarcomas of the great vessels in CT, MRI and (18)F-FDG PET/CT. METHODS: Thirteen patients with a primary sarcoma of the great vessels were retrospectively evaluated. All available images studies including F-18 FDG PET(/CT) (n = 4), MDCT (n = 12) and MRI (n = 6) were evaluated and indicative image features of this rare tumor entity were identified. RESULTS: The median interval between the first imaging study and the final diagnosis was 11 weeks (0-12 weeks). The most frequently observed imaging findings suggestive of malignant disease in patients with sarcomas of the pulmonary arteries were a large filling defect with vascular distension, unilaterality and a lack of improvement despite effective anticoagulation. In patients with aortic sarcomas we most frequently observed a pedunculated appearance and an atypical location of the filling defect. The F-18 FDG PET(/CT) examinations demonstrated an unequivocal hypermetabolism of the lesion in all cases (4/4). MRI proved lesion vascularization in 5/6 cases. CONCLUSION: Intravascular unilateral or atypically located filling defects of the great vessels with vascular distension, a pedunculated shape and lack of improvement despite effective anticoagulation are suspicious for primary sarcoma on MDCT or MRI. MR perfusion techniques can add information on the nature of the lesion but the findings may be subtle and equivocal. F-18 FDG PET/CT may have a potential role in these patients and may be considered as part of the imaging workup.

A novel imaging system permits real-time in vivo tumor bed assessment after resection of naturally occurring sarcomas in dogs.

BACKGROUND: Treatment of soft tissue sarcoma (STS) includes complete tumor excision. However, in some patients, residual sarcoma cells remain in the tumor bed. We previously described a novel hand-held imaging device prototype that uses molecular imaging to detect microscopic residual cancer in mice during surgery. QUESTIONS/PURPOSES: To test this device in a clinical trial of dogs with naturally occurring sarcomas, we asked: (1) Are any adverse clinical or laboratory effects observed after intravenous administration of the fluorescent probes? (2) Do canine sarcomas exhibit fluorescence after administration of the cathepsin-activated probe? (3) Is the tumor-to-background ratio sufficient to distinguish tumor from tumor bed? And (4) can residual fluorescence be detected in the tumor bed during surgery and does this correlate with a positive margin? METHODS: We studied nine dogs undergoing treatment for 10 STS or mast cell tumors. Dogs received an intravenous injection of VM249, a fluorescent probe that becomes optically active in the presence of cathepsin proteases. After injection, tumors were removed by wide resection. The tumor bed was imaged using the novel imaging device to search for residual fluorescence. We determined correlations between tissue fluorescence and histopathology, cathepsin protease expression, and development of recurrent disease. Minimum followup was 9 months (mean, 12 months; range, 9-15 months). RESULTS: Fluorescence was apparent from all 10 tumors and ranged from 3 × 10(7) to 1 × 10(9) counts/millisecond/cm(2). During intraoperative imaging, normal skeletal muscle showed no residual fluorescence. Histopathologic assessment of surgical margins correlated with intraoperative imaging in nine of 10 cases; in the other case, there was no residual fluorescence, but tumor was found at the margin on histologic examination. No animals had recurrent disease at 9 to 15 months. CONCLUSIONS: These initial findings suggest this imaging system might be useful to intraoperatively detect residual tumor after wide resections. CLINICAL RELEVANCE: The ability to assess the tumor bed intraoperatively for residual disease has the potential to improve local control.

Technical innovation in dynamic contrast-enhanced magnetic resonance imaging of musculoskeletal tumors: an MR angiographic sequence using a sparse k-space sampling strategy.

OBJECTIVE: We demonstrate the clinical use of an MR angiography sequence performed with sparse k-space sampling (MRA), as a method for dynamic contrast-enhanced (DCE)-MRI, and apply it to the assessment of sarcomas for treatment response. MATERIALS AND METHODS: Three subjects with sarcomas (2 with osteosarcoma, 1 with high-grade soft tissue sarcomas) underwent MRI after neoadjuvant therapy/prior to surgery, with conventional MRI (T1-weighted, fluid-sensitive, static post-contrast T1-weighted sequences) and DCE-MRI (MRA, time resolution = 7-10 s, TR/TE 2.4/0.9 ms, FOV 40 cm(2)). Images were reviewed by two observers in consensus who recorded image quality (1 = diagnostic, no significant artifacts, 2 = diagnostic, <25 % artifacts, 3 = nondiagnostic) and contrast enhancement characteristics by static MRI (presence/absence of contrast enhancement, percentage of enhancement) and DCE-MRI (presence/absence of arterial enhancement with time-intensity curves). Results were compared with histological response (defined as <5 % viable tumor [soft tissue sarcoma] or <10 % [bone sarcoma] following resection). RESULTS: Diagnostic quality for all conventional and DCE-MRI sequences was rated as 1. In 2 of the 3 sarcomas, there was good histological response (≤5 % viable tumor); in 1 there was poor response (50 % viable tumor). By static post-contrast T1-weighted sequences, there was enhancement in all sarcomas, regardless of response (up to >75 % with good response, >75 % with poor response). DCE-MRI findings were concordant with histological response (arterial enhancement with poor response, no arterial enhancement with good response). CONCLUSION: Unlike conventional DCE-MRI sequences, an MRA sequence with sparse k-space sampling is easily integrated into a routine musculoskeletal tumor MRI protocol, with high diagnostic quality. In this preliminary work, tumor enhancement characteristics by DCE-MRI were used to assess treatment response.

Gemcitabine, docetaxel, and bevacizumab in relapsed and refractory pediatric sarcomas.

BACKGROUND: The outcome for patients with relapsed and refractory pediatric sarcomas remains dismal. Novel agents are needed to improve overall survival in these patients. OBSERVATIONS: We present 3 patients with relapsed/refractory sarcomas treated with gemcitabine, docetaxel, and bevacizumab in 3-week cycles. The combination was well tolerated with minimal toxicity. Two patients had a partial response and the third patient had stable disease for >6 months. CONCLUSIONS: These results are limited by small patient numbers but this strategy should be evaluated in prospective clinical trials.

Photodynamic induced uptake of liposomal doxorubicin to rat lung tumors parallels tumor vascular density.

BACKGROUND: Visudyne®-mediated photodynamic therapy (PDT) at low drug/light conditions has shown to selectively enhance the uptake of liposomal doxorubicin in subpleural localized sarcoma tumors grown on rodent lungs without causing morphological alterations of the lung. The present experiments explore the impact of low-dose PDT on liposomal doxorubicin (Liporubicin™) uptake to different tumor types grown on rodent lungs. MATERIAL AND METHODS: Three groups of Fischer rats underwent subpleural generation of sarcoma, mesothelioma, or adenocarcinoma tumors on the left lung. At least five animals of each group (sarcoma, n = 5; mesothelioma, n = 7; adenocarcinoma, n = 5) underwent intraoperative low-dose (10 J/cm(2) at 35 mW/cm(2) ) PDT with 0.0625 mg/kg Visudyne® of the tumor and the lower lobe. This was followed by intravenous (IV) administration of 400 µg Liporubicin™. After a circulation time of 60 min, the tumor-bearing lung was processed for HPLC analyses. At least five animals per group underwent the same procedure but without PDT (sarcoma, n = 5; mesothelioma, n = 5; adenocarcinoma, n = 6). Five untreated animals per group underwent CD31 immunostaining of their tumors with histomorphometrical assessment of the tumor vascularization. RESULTS: Low-dose PDT significantly enhanced Liporubicin™ uptake to all tumor types (sarcoma, P = 0.0007; mesothelioma, P = 0.001; adenocarcinoma, P = 0.02) but not to normal lung tissue compared to IV drug administration alone. PDT led to a significantly increased ratio of tumor to lung tissue drug uptake for all three tumor types (P < 0.05). However, the tumor drug uptake varied between tumor types and paralleled tumor vascular density. The vascular density was significantly higher in sarcoma than in adenocarcinoma (P < 0.001) and mesothelioma (P < 0.001), whereas there was no significant difference between adenocarcinoma and mesothelioma. CONCLUSION: Low-dose Visudyne®-mediated PDT selectively enhances the uptake of systemically administered liposomal doxorubicin in tumors without affecting the drug uptake to normal lung. However, drug uptake varied significantly between tumor types and paralleled tumor vascular density.

Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts.

E7080 is an inhibitor of multiple tyrosine kinases, several of which have pro-angiogenic properties, including receptors for VEGF, FGF, SCF and PDGF. We undertook our study to evaluate the preclinical activity of E7080 in human sarcomas. The antitumour activity of orally administered E7080 was tested in ten human tumour xenografts representing different sarcoma histotypes. Concomitant changes in microvessel density were assayed by immunohistochemistry to CD31. Immunohistochemistry was also used to assess the expression of kinases that E7080 is known to inhibit. The MTS assay was applied to determine effects on tumour cell viability in vitro. At the Q1D5 × 2 schedule, E7080 (30 mg/kg) was active (T/C<40%) in 7/10 xenografts. The effects were accompanied by marked decrease in microvessel densities. Given at the Q1D5 × 4 schedule, E7080 (30, 10, 3 mg/kg) showed antitumour activity in a dose dependent manner in two different xenografts. E7080 growth inhibition did not correlate with the expression of VEGFR1-3, PDGFRA, PDGFRB, FGFR1 or KIT on tumour cells but was significantly correlated with expression of VEGFR2 on tumour microvessels. In vitro E7080 did not show potent effects on tumour cell viability in four different sarcoma cell lines, with IC50 values ≥ 10 µM. In conclusion, E7080 showed broad in vivo antitumour activity in sarcoma, mainly attributable to angiogenesis inhibition. E7080 was also active in xenografts resistant to one or more clinically relevant reference drugs given at MTD (doxorubicin, cisplatin or ifosfamide). The present results encourage further investigation of a potential role of E7080 in sarcoma therapy in the clinic.