Ayumi Seko

An initial clinical study on the efficacy of cisplatin-releasing gelatin microspheres for metastatic liver tumors

PURPOSE To evaluate the antitumor effect and side effects of cisplatin-releasing gelatin microspheres (Cis-GMSs) for metastatic liver tumors. METHODS Cis-GMSs that degraded over 14 days were employed. The subjects comprised a total of nine cases. Transcatheter hepatic artery embolization (TAE) using Cis-GMSs (Cis-GMSs-TAE) was performed 13 times in total. Six cases, each containing one to five tumors in a single segment to an entire lobe were treated by Cis-GMSs-TAE. In the remaining three cases with six or more metastatic liver tumors, the right and left lobes were treated by Cis-GMSs-TAE at a 2-week interval. RESULTS There were two complete response (CR), one partial response (PR) and six stable disease (SD) cases. The response rate was 33.3%. The average rate of reduction in tumor diameter was 32%. Disappearance of metastatic liver tumors was observed in only two of the nine cases. As for side effects and complications, post-embolization syndrome was observed in eight cases, but no severe complications such as cholangitis or liver abscess were observed. CONCLUSION Considering the mild side effects by Cis-GMSs-TAE, it is suggested that Cis-GMSs-TAE should be tried at least once as topical therapy for metastatic liver tumors when the response to systemic chemotherapy and other treatments is not satisfactory.

Prolonged local persistence of cisplatin-loaded gelatin microspheres and their chemoembolic anti-cancer effect in rabbits

PURPOSE To confirm prolonged cisplatin release from drug-loaded gelatin microspheres (GMSs) and their improved chemoembolic anti-cancer effect against VX2 liver tumors in rabbits. MATERIALS AND METHODS Two groups of twelve rabbits each were treated intraarterially either with 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) or 0.04 mg/kg cisplatin solution by administering them into the right renal artery. Platinum concentrations within the renal parenchyma were analyzed immediately following infusion (day 0) and on days 1, 3, and 7 using the atomic absorption method. In a second experiment four groups of five rabbits each with implanted VX2 liver tumors were treated intraarterially through the hepatic artery with the following drugs: 2 mg/kg cisplatin-loaded GMSs (=0.04 mg/kg cisplatin) (group I), 2 mg/kg GMSs without any drug (group II), 1.5 mg/kg cisplatin solution (group III) and saline (group IV). Tumor volumes were analyzed pre-injection and 7 days after with MRI allowing calculating the relative tumor growth rate (%). Degree of liver cell necrosis was assessed on the histopathological specimens. RESULTS The renal parenchymal platinum concentrations (microg/ml) with 4.51+/-2.25 (day 0), 1.59+/-0.70 (day 1), 0.72+/-0.10 (day 3) and 0.20+/-0.06 (day 7) were significantly more pronounced after cisplatin-loaded GMS on days one and three compared to cisplatin with 1.99+/-0.55, 0.08+/-0.03, 0.18+/-0.01 and 0.10+/-0.07, respectively. Relative tumor growth rates resulted in 84.5%+/-26.4 (group I); 241.4%+/-145.1 (II); 331.9%+/-72.2 (III), and 413.6%+/-103.6 (IV) with statistical significant differences between groups I and III, and groups I and IV. Similar degrees of necrosis were observed in both GMSs treated groups, while ballooning of hepatocytes was highest in cisplatin-loaded GMSs. CONCLUSIONS With cisplatin-loaded GMSs more pronounced and prolonged local parenchymal cisplatin concentrations may be achieved offering the advantage of an increased and prolonged anti-cancer effect compared to cisplatin alone or controls. Moreover this proves indirectly the breakdown and release of cisplatin from the GMSs which is of primary importance for drug delivery systems.

Embolization Materials Made of Gelatin: Comparison Between Gelpart and Gelatin Microspheres

Purpose:The object of this study was to assess the level of embolization in the embolized artery and the degradation period of these two embolic agents in the renal arteries using rabbit models.Materials and Methods: The renal artery was embolized using 5 mg of gelatin microspheres (GMSs; diameter, 35–100 μm; group 1) or 1 mg of Gelpart (diameter, 1 mm; group 2). For each group, angiographies were performed on two kidneys immediately after the embolic procedure and on days 3, 7, and 14 after embolization. This was followed by histopathological examinations of the kidneys.Results:Follow-up angiograms on each day revealed the persistence of poorly enhanced wedge-shaped areas in the parenchymal phase in all cases. In group 1, four of six cases showed poorly enhanced small areas in the follow-up angiograms. In group 2, all cases showed poorly enhanced large areas. In the histopathological specimens, it was observed that immediately after embolization, the particles reached the interlobular arteries in group 1 and the interlobar arteries in group 2. In all cases in group 1, the particles were histologically identified even on day 14. In one case in group 2 on day 14, the particles were not identified.Conclusion:In conclusion, although GMSs and Gelpart were similar in the point of gelatin particles, the level of embolization and the degradation period were different between GMSs and Gelpart.

Cisplatin-conjugated degradable gelatin microspheres: fundamental study in vitro

The object of this study was to generate cisplatin-conjugated gelatin microspheres (GMSs) and to confirm the subsequent release of cisplatin in vitro. The GMSs (1 mg) were immersed in 50 microl of a cisplatin solution (0.06, 0.15, 0.27, 0.30 or 0.54 mg ml(-1)) at 38 degrees C to allow conjugation. The cisplatin-conjugated GMSs were then extensively washed in double-distilled water and freeze-dried. The platinum concentration in the GMSs samples was investigated as a function of the concentration of cisplatin solution used in their preparation, the number of immersions in cisplatin (1, 2, 3, 4 or 5) and the period of immersion (1, 6 or 11 h). In vitro release tests were performed at different time intervals (1, 3, 6, 12 or 24 h) to allow the rate of cisplatin release to be calculated. The platinum concentration of the GMSs increased in proportion to the concentration of cisplatin solution and the length or number of immersions in cisplatin. In vitro release tests demonstrate that the release rate (%) from GMSs after 1, 3, 6, 12 or 24 h was 4.8, 5.5, 7.6, 10.0 and 12.4, respectively. We demonstrated the ability of GMSs to bind cisplatin forming cisplatin-conjugated GMSs. Moreover, we showed that cisplatin continued to bind GMSs strongly during the in vitro release test.

A combination of cisplatin-eluting gelatin microspheres and flavopiridol enhances anti-tumour effects in a rabbit VX2 liver tumour model.

The aim of this study was to investigate whether the combination of cisplatin-eluting gelatin microspheres (GMSs) and flavopiridol enhances anti-tumour effects in a rabbit VX2 liver tumour model. Tumour-bearing rabbits (n = 21) were divided into five groups and infused from the proper hepatic artery. Group 1 (n = 5) received cisplatin-eluting GMSs (1 mg kg(-1)) and flavopiridol (3 mg kg(-1)), group 2 (n = 5) cisplatin-eluting GMSs alone (1 mg kg(-1)), Group 3 (n = 5) flavopiridol (3 mg kg(-1)), Group 4 (n = 3) GMSs alone (1 mg kg(-1)), and Group 5 (n = 3) was the control group receiving physiological saline (1 ml kg(-1)). On days 0 and 7 after procedures the liver tumour volume was measured using a horizontal open MRI system and the relative tumour volume growth rates for 7 days after treatment were calculated. On T(1) weighted images, the tumours were visualised as circular, low-intensity areas just below the liver surface. After treatment, the signals remained similar. The relative tumour volume growth rate for 7 days after treatment was 54.2+/-22.4% in Group 1, 134.1+/-40.1% in Group 2,166.7+/-48.1% in Group 3, 341.8+/-8.6% in Group 4 and 583.1+/-46.9% in Group 5; the growth rate was significantly lower in Group 1 than the other groups (p<0.05). We concluded that in our rabbit model of liver tumours the combination of cisplatin-eluting GMSs and flavopiridol was effective.

Vascular Regeneration by Repeated Infusions of Basic Fibroblast Growth Factor in a Rabbit Model of Hind-Limb Ischemia

OBJECTIVE Regenerative therapy is a new treatment of vascular occlusive diseases. The purpose of this study was to examine the advantages of repeated low-dose growth factor infusions compared with a single high-dose infusion in an ischemic hind-limb rabbit model. MATERIALS AND METHODS Thirty-two rabbits were used to construct an ischemic hind-limb model by resection of the left femoral artery. For the vascular regenerative method, basic fibroblast growth factor (bFGF) was impregnated into 3 mg of gelatin microspheres 30 microm in diameter and a reservoir system was implanted in the left femoral artery for infusion. The gelatin microspheres were then infused into the left internal iliac artery via the reservoir system. The rabbits were divided into three groups according to different infusion methods: single high-dose infusion, repeated low-dose infusions, and saline (control). Therapeutic effects were evaluated by thigh temperature, blood pressure, blood flow, angiography, and pathology. RESULTS There was no significant difference between the two infusion methods in thigh temperature, blood pressure, blood flow, angiography, and pathology. In pathologic analyses at 2 and 4 weeks, both the repeated low-dose infusion and the single high-dose infusion groups showed significant differences in the number of vessels when compared with the control group. CONCLUSION The efficacy of repeated bFGF infusions for neovascularization via the reservoir method was investigated. Despite the pathologic confirmation of neovascularization, there was no significant difference in treatment effect by the two administration methods.

Cisplatin‐conjugated Gelpart: initial study in vitro

Aim:  In Japan, Gelpart (Nippon Kayaku, Tokyo, Japan) is commercially available as an embolic agent made of gelatin for hepatocellular carcinoma. The object of this study was to develop cisplatin‐conjugated Gelpart, confirm its bonding capability and confirm cisplatin‐release from it in vitro.

Development of a conjugated gadolinium and cisplatin–gelatin possessing properties as an intravascular contrast agent for MR imaging

PURPOSE The purpose of this study is to create a Gd-DTPA-Gel-Cis compound, which made from gadolinum (Gd), diethylenetriaminepentaacetic acid (DTPA)-dianhydride, cis-diamminedichloroplatinum (Cis) and bovine gelatin (Gel), that makes it possible to visualize Cis as intravascular agent under magnetic resonance imaging (MRI). MATERIALS AND METHODS The amount of DTPA, Gd, and Cis were titrated to determine the new compounds conjugation ratio with gelatin. Considering these functions, Gd-DTPA-Gel-Cis was synthesized, and its stability in bovine serum was evaluated. In addition, the signal intensity of the diluted sample was measured under 1.5 Tesla MRI. RESULTS The synthesized 10mg/ml of Gd-DTPA-Gel-Cis contained 42.84 microg/ml of Gd and 1.53 microg/ml of platinum. Gd-DTPA-Gel-Cis (100 mg/10 ml) enclosed into the cellulose dialysis tubing was placed in 90 ml of bovine serum and shaken reciprocally at 72 stroke/min at 37 degrees C. Partial release of free Pt was shown at 6 and 24 h, but no release of Gd occurred for a 24-h period. And high stability of Gd conjugated to DTPA-Gel-Cis. This result suggests possible anti-tumor effectiveness and high stability of Gd conjugated to DTPA-Gel-Cis. The diluted sample presented high signal intensity under 1.5 Tesla MRI. CONCLUSION Gd-DTPA-Gel-Cis has been developed successfully and we have proven its stability and contrast ability in MRI.

Edaravone prevents bowel infarction after acute superior mesenteric artery thromboembolism using autologous fibrin clots in a rabbit model

The aim of this study was to evaluate the effects of intra-arterial administration of edaravone after superior mesenteric artery (SMA) thromboembolism in a rabbit model. 24 Japanese white rabbits were randomly allocated to a urokinase group (group U) and a urokinase with edaravone group (group E). A further three rabbits, which were administered an autologous blood clot alone, served as a control group (group C). A 4-Fr sheath was inserted into an SMA. An autologous blood clot was administered to an SMA (group C). After 45 min, urokinase (6000 IU) and heparin (250 IU) were administered through the catheter, either alone (group U) or in conjuction with edaravone (0.5 mg kg(-1)) (group E). In eight rabbits from each of groups U and E, 6 h after reperfusion, the small intestine was harvested and divided into five equal parts. The degree of intestinal tissue injury in each part was rated on a scale of 0-8. After 1 week, survival times and blood biochemistry data were compared among rabbits in group U (four rabbits), group E (four rabbits) and group C (three rabbits), and significant differences (p<0.05) were recorded. Intestinal mucosal damage was significantly greater in group U (5.8 +/- 1.5) than in group E (2.9 +/- 0.7). Survival time tended to be longer in group E (p>0.4, not significant compared with group U). Liver and kidney function showed signs of deterioration over time whether or not edaravone was administered, but administration of edaravone reduced intestinal mucosal damage. An increase in survival rate requires improvements in evaluation methods to enable identification of ischaemic areas.

Ability of chest X-ray to detect faint shadows documented as ground-glass attenuation in images of computed tomography: A comparison between flat-panel detector radiography and film-screen radiography

PURPOSE To compare flat-panel detector (FPD) radiography and film-screen (FS) radiography in detectability of faint shadows documented as ground-glass attenuation (GGA) areas in images of computed tomography (CT). MATERIALS AND METHODS Study population was comprised of 50 patients who underwent FS and another 50 patients who underwent FPD. Standard of reference (SOR) was determined on the basis of area of GGA in all cross-sections of CT, in terms of GGA extent and presence or absence of GGA in each trisected lung fields (GGA distribution). Eight radiologists assessed the GGA extent with the 5-grade scale and the GGA distribution. Inter-observer variances of the GGA extents and distributions, degree of divergences and correspondence in the GGA extent and distributions with SOR, were compared between the FS and FPD by the jackknife method and Fishers exact test. RESULTS Inter-observer variance in the GGA extent and distribution were slightly larger in the FS than in the FPD. The GGA extent scale corresponded with SOR in the FS statistically significantly better (p=0.001), as the correct ratio was 0.428 in the FS and 0.310 in the FPD. Divergence in the GGA extent scale with SOR was smaller in the FS, as average kappa pseudo-value of Kendalls rank correlation coefficient was 0.474 in the FS and 0.433 in the FPD. CONCLUSION These results indicate that some lesions of GGA documented in CT may not be reflected and are difficult to be detected in chest X-ray radiographs with the FPD.