three types of calibrated microspheres have recently been approved in japan as embolic agents for hypervascular tumors and arteriovenous malformations . to date , two types of embolic microspheres capable of being loaded with drug have been introduced : dc bead ( biocompatibles , farnham , uk ) and hepasphere ( biosphere medical , roissy cdg cedex , france ) . in a phase
ii randomized controlled study of transarterial chemoembolization ( tace ) using a drug - eluting bead ( deb - tace ) for hepatocellular carcinoma ( hcc ) , the precision - v study , the response rate after 6 months was 52% in the deb - tace group and 44% in the tace group using a lipiodol ( laboratoire guerbet , aulnay - sous - bois , france)/anticancer drug mixture solution ( lip - tace ) , showing no significant difference or superiority of deb - tace .
however , complication by postembolization syndrome , such as abdominal pain , fever , nausea , vomiting and liver enzyme elevation , developed in 2080% after lip - tace [ 3 , 4 ] , whereas symptoms developed in only 1837% after deb - tace [ 5 , 6 ] , showing that the complications were milder than those after lip - tace . on the other hand , deb - tace induced liver abscesses at a relatively high frequency , which could be fatal [ 5 , 7 , 8 , 9 ] .
adverse events after deb - tace have been reported occasionally [ 5 , 7 , 8 , 9 , 10 , 11 ] , but as it has just been introduced in japan , many points regarding adverse events are unclear with respect to the developmental mechanism and risk factors .
we encountered a hcc patient who underwent deb - tace and experienced delayed intratumoral hemorrhage .
an 81-year - old male regularly visited his physician for treatment of hepatitis c virus - related cirrhosis . on routine abdominal ultrasonography ( us ) ,
on esophagogastroduodenoscopy , a type 0-iia early gastric carcinoma with a diameter of 25 mm was detected in the lesser curvature of the middle body .
the patient was referred to our hospital for further examination and treatment . during the first examination ,
the liver function was classified as child - pugh class a , and the tumor markers were normal ( afp level : 3.4 ng / ml , afp - l3 fraction level < 0.5% ) , but the pivka ii had a level of 118 mau / ml , showing a mild elevation .
it was capsulated and enhanced in the arterial phase on dynamic computed tomography ( ct ) ( fig .
1 ) , and showed a mosaic pattern accompanied by a marginal hypoechoic zone on gray - scale us .
the mass was enhanced in the vascular phase ( 040 s ) on contrast - enhanced us ( ceus ) using sonazoid ( daiichi sankyo , tokyo , japan ) , and showed a hypoechoic area in the postvascular phase ( 10 min after an intravenous injection of sonazoid ) .
based on the tumor marker and imaging findings , the patient was diagnosed with hcc .
deb - tace was performed because the patient declined to undergo surgical resection of hcc .
access for tace was performed under sterile conditions and under local anesthesia , via the right femoral artery using a 3-fr sheath ( medikit , tokyo , japan ) and in a retrograde fashion .
when a microcatheter was advanced to the anterior segmental artery of the right hepatic artery and contrast imaging was applied , an intensely stained tumor was observed , with a5 as the feeding artery . a solution impregnated with 100300 m dc bead and 50 mg epirubicin hydrochloride , with a dc bead volume of 0.35 ml , was administered via the feeding artery to perform deb - tace .
disappearance of the intensely stained tumor image was confirmed by right hepatic arterial angiography , and the treatment was completed .
the course after deb - tace was favorable , and no adverse events above grade 3 according to the common terminology criteria for adverse events ( ctcae ) version 4.0 were observed .
endoscopic submucosal dissection ( esd ) of the early gastric carcinoma was performed about 1 month after deb - tace .
right hypochondriac pain suddenly developed 3 days after esd , but no adverse events were assumed to be caused by esd ( i.e. , free air , noted on dynamic ct ) .
however , the tumor diameter had increased from that before deb - tace , and the tumor showed a high - intensity area on unenhanced ct ( fig .
2a ) , which was not enhanced in the arterial phase on dynamic ct , suggesting intratumoral hemorrhage .
the hemodynamics of the tumor were followed using ceus over the time before and after deb - tace .
on ceus carried out on the day after deb - tace , the whole intratumoral enhancement decreased , and nonenhanced patchy regions , assumed to be necrosis , were noted in the tumor in the vascular phase . on ceus
performed 4 weeks after deb - tace , i.e. , immediately before esd , the tumor size was 33  31 mm , and the enhancement area was increased in the vascular phase ( fig .
however , the tumor had enlarged to 41  36 mm on ceus when the right hypochondriac pain developed ( 5 weeks after deb - tace ) , and changes in the echogenicity on gray - scale us and nonenhancement of almost the entire tumor in the vascular phase on ceus were noted ( fig .
based on the above findings , the cause of right hypochondriac pain may have been deb - tace - associated intratumoral hemorrhage .
since the hemorrhage was limited to inside the tumor , it stopped spontaneously with rest .
the advantages of deb - tace are as follows : the infusion dose of the chemotherapeutic agent can be modified by adjusting the chemotherapeutic agent carrier , while altering the depth of embolization with beads , the duration of tumor exposure to chemotherapeutic agent can be fine - tuned through sustained release of the chemotherapeutic agent , and systemic adverse reactions of chemotherapeutic agent can be attenuated by continuous release of high - dose chemotherapeutic agents into the tumors .
deb has proven to be extremely potent and safe by allowing large amounts of the chemotherapeutic agent to concentrate within the tumor over time , thereby maximizing the cytotoxic effect , which also makes it attractive as an effective treatment for large lesions .
favorable therapeutic effects have been reported occasionally [ 8 , 9 ] and have increased the expectations of hcc treatment with deb - tace ; however , the beads exhibit characteristic physical properties and behavior that are different from those of gelatin particles .
it is important to fully investigate these characteristics to avoid inadequacy of the therapeutic effect and to prevent the onset of adverse events .
previous studies have reported that the incidence of mild adverse events , such as postembolization syndrome , is lower in the deb - tace group compared with the lip - tace group [ 3 , 4 , 5 , 6 ] .
meanwhile , liver abscesses were induced at a relatively high frequency ( about 1.67.4% ) [ 5 , 7 , 8 , 9 ] .
malagari et al .   reported that the 30-day mortality was 1.26% among 237 hcc patients treated with deb - tace with dc bead loaded with doxorubicin , and that the cause was liver abscess in all cases .
regarding other adverse events , acute pancreatitis and cholecystitis developed with incidences of 15 and 16.3% , respectively .
previous studies have shown that rare adverse events included liver failure and infection , bile duct injury , upper gastrointestinal bleeding , pulmonary embolism , splenic infarction , or spinal embolization [ 1 , 7 , 10 , 11 ] .
unlike lip - tace , many adverse events occurred due to ischemic changes induced by the inflow of beads into organs other than the hcc lesion , which is characteristic of deb - tace .
tumor hemorrhage has also been reported after deb - tace [ 1 , 7 , 10 , 11 , 13 ] with large tumors , with a diameter of 516 cm , and the tumor locations were subcapsular in all previous reports . to our knowledge , there has been no case of a tumor with a diameter < 5 cm distinct from the subcapsular , as was observed in our patient .
there has been no report of a mechanism underlying the deb - tace - specific tumor hemorrhage . in general
, the mechanism of tumor rupture after tace might be related to increased intratumoral pressure as a result of rapid edematic expansion due to tumor necrosis or vascular injury , secondary to embolization .
the risk is particularly high in subcapsular lesions , and we must be careful because the spread of hemorrhage in the abdominal cavity can not only lead to hemorrhagic shock , but also peritoneal metastasis .
unlike the reported cases of tumor hemorrhage after deb - tace , in the present case , the tumor diameter was not large and the tumor was distinct from the subcapsular region .
however , intratumoral hemorrhage occurred about 1 month after deb - tace . local pooling of the contrast agent within the target tumor could occur during deb - tace , and seki et al .  
reported that it occurred in 25.2% of 135 hcc patients treated with deb - tace ( epirubicin - loaded hepasphere ) .
while the cause of this local pooling remains unclear , it is similar to extravasation or blood sinus , suggesting that it was a local hemorrhage due to intratumor vascular collapse as a consequence of the treatment .
when local pooling of the contrast agent was noted , seki et al .   added a small amount of gelatin sponge particles , with a diameter ranging from 1 to 2 mm , to the feeding artery until the pooling disappeared .
based on the above findings , the observation of local pooling of the contrast agent within the target tumor during treatment suggests that intratumoral pressure has already increased , which was unlikely in our patient .
treatment - induced intratumoral hemorrhage continued immediately after deb - tace because no pooling was noted during treatment or on confirmation angiography following treatment .
however , it is possible that the amount of dc bead was insufficient and embolization was incomplete .
it was assumed that incomplete embolization subsequently caused intratumoral vascular collapse , i.e. , a phenomenon similar to pooling , and that the hemorrhage expanded to the necrotic intratumoral area by sustained release of the chemotherapeutic agent and embolization , leading to complication of intratumoral hemorrhage despite the low risk of tumor hemorrhage .
many points remain unclear , i.e. , the appropriate bead sizes for each case and the level of embolization , but it may be important to apply sufficient embolization because insufficient embolization is likely to lead to tumor hemorrhage .
deb - tace is considered to rarely cause adverse events , but fatal complications have been reported [ 5 , 7 , 8 , 9 ] , and reports of adverse events may increase with augmentation of the numbers of deb - tace - treated patients . if reports of tumor hemorrhage after deb - tace increase , the mechanism of intratumoral hemorrhage in cases similar to our patient may be elucidated .
intratumoral hemorrhage was suspected due to the presence of a high - intensity area in the tumor on unenhanced ct and a rapid increase in the tumor diameter and accompanying enlargement of the unenhanced area on ceus performed before and after deb - tace . based on these findings
it was difficult to assess the therapeutic effect of deb - tace by ct , based on lipiodol accumulation , unlike that after conventional lip - tace , and evaluation of the intratumoral hemodynamics could be important .
ceus is superior in evaluating intratumoral hemodynamics in real time , and the utility of ceus to evaluate the therapeutic effect after deb - tace was suggested .
we encountered a patient who experienced intratumoral hemorrhage about 1 month after deb - tace .
deb - tace for hcc is a new treatment method in japan , and reports of adverse events may increase in the future . to obtain the therapeutic effect of deb - tace while preventing the adverse events , it may be important to understand the characteristics of the beads themselves and to apply the appropriate embolization to each individual case .
it was also suggested that ceus is useful to evaluate the therapeutic effect after deb - tace .
 transarterial chemoembolization ( tace ) using a drug - eluting bead ( deb - tace ) for hepatocellular carcinoma ( hcc ) is a new treatment method . 
 we report on a case of delayed intratumoral hemorrhage after deb - tace . 
 an 81-year - old male with hepatitis c virus - related cirrhosis was diagnosed with a hcc of 35 mm in diameter in s5 detected by dynamic computed tomography ( ct ) and contrast - enhanced ultrasonography ( ceus ) . 
 deb - tace with dc bead and epirubicin hydrochloride was performed because the patient declined to undergo surgical resection . 
 the treatment was completed , and the course after deb - tace was favorable . however , right hypochondriac pain suddenly developed about 1 month after deb - tace . 
 unenhanced ct showed an increase of the tumor diameter and intratumoral high - intensity area , which was not enhanced in the arterial phase . 
 ceus performed at the time of right hypochondriac pain ( 5 weeks after deb - tace ) showed nonenhancement of almost the entire tumor in the vascular phase . 
 the cause of the symptom may have been deb - tace - associated intratumoral hemorrhage . 
 tumor hemorrhage has been reported after deb - tace with tumors > 5 cm in diameter , and the tumor locations were subcapsular in all previous reports . there has been no case of a tumor with a diameter < 5 cm distinct from the subcapsular , as was observed in our patient . 
 incomplete embolization might be the cause of the intratumoral hemorrhage experienced by this case presenting a few risks . to obtain the therapeutic effect of deb - tace while preventing the adverse events 
 , it may be important to understand the characteristics of the beads and to apply the appropriate embolization to each individual case . 