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1549
Limited but Definite Efficacy of Prophylactic Hepatic
Arterial Infusion Chemotherapy after Curative
Resection of Colorectal Liver Metastases
A Randomized Study
Takeshi Tono, M.D., Ph.D.1,2
Yasunori Hasuike, M.D., Ph.D.1
Hiroki Ohzato, M.D., Ph.D.2
Yuichi Takatsuka, M.D., Ph.D.2
Nobuteru Kikkawa, M.D., Ph.D.1
1
Department of Surgery, Osaka National Hospital,
Osaka, Japan.
2
Department of Surgery, Kansai Rosai Hospital,
Hyogo, Japan.
Supported in part by a grand-in-aid for cancer
research from the Ministry of Health and Welfare
(6-17), Japan.
The authors are grateful to Yuika Kanaishi, Ph.D.,
for her help in preparing the article.
Address for reprints: Takeshi Tono, M.D., Ph.D.,
Department of Surgery, NTT West Osaka Hospital,
2-6-40 Karasugatsuji, Tennoji-ku, Osaka, Osaka
543-8922, Japan.
Received February 17, 1999; revisions received
July 16, 1999, and November 29, 1999; accepted
November 29, 1999.
© 2000 American Cancer Society
BACKGROUND. Greater than 50% of patients who undergo curative resection of liver
metastases from colorectal carcinoma develop recurrent disease in the residual
liver. Although several studies have attempted to use hepatic arterial infusion (HAI)
chemotherapy to prevent recurrence, to the authors’ knowledge the efficacy of the
treatment has not yet been determined.
METHODS. Nineteen patients who underwent curative hepatectomy for metastatic
colorectal carcinoma randomly were assigned into the HAI group (nine patients) or
the control group (ten patients). Patients in the HAI group received continuous
intraarterial infusion of 5-fluorouracil (5-FU) (500 mg/day) for 4 days followed by
a 3-day rest. The treatment was continued for 6 weeks.
RESULTS. The median follow-up period was 62.2 months. The recurrence was
confirmed in three patients in the HAI group and in eight patients in the control
group. Of these, recurrence in the remnant liver was observed in one patient and
in six patients, respectively. The median disease free interval after hepatectomy
was 62.6 months in the HAI group and 13.8 months in the control group. The
1-year, 2-year, and 3-year disease free survival rates were 77.8%, 77.8%, and 66.7%,
respectively, in the HAI group and 50.0%, 30.0%, and 20.0%, respectively, in the
control group. Significant prolongation of disease free survival was observed in the
HAI group (P ⫽ 0.045). No patients in the HAI group reported any adverse effect of
ⱖ Grade 2 (according to the National Cancer Institute Common Toxicity Criteria).
Two patients in the HAI group and five patients in the control group were dead of
disease at the time of last follow-up. The 1-year, 3-year, and 5-year cumulative
survival rates for the HAI group were 88.9%, 77.8%, and 77.8%, respectively,
whereas those of the control group were 100.0%, 50.0%, and 50.0%, respectively
(P ⫽ 0.2686).
CONCLUSIONS. This randomized study revealed that short term HAI of 5-FU after
curative resection of colorectal hepatic metastases is effective in preventing the
recurrence of disease without any serious complications. Cancer 2000;88:1549 –56.
© 2000 American Cancer Society.
KEYWORDS: colorectal carcinoma, liver metastases, adjuvant chemotherapy, hepatic arterial infusion, 5-fluorouracil, fluoropyrimidines, curative resection, regional
chemotherapy, randomized study.
H
epatic resection is potentially regarded as the only curative treatment for liver metastases originating from colorectal carcinoma,
and the 5-year survival rate after hepatectomy has been reported to
range from 25– 45%.1–5 However, approximately 60 –75% of patients
1550
CANCER April 1, 2000 / Volume 88 / Number 7
develop recurrent disease after curative tumor resection and ⬎ 50% develop recurrent lesions in the residual liver.1–5
Fluoropyrimidines have been known as one of the
most effective chemotherapeutic agents against colorectal carcinoma6 and are widely used for postoperative adjuvant chemotherapy via a systemic route.7,8 In
addition, fluoropyrimidines have been administered
locally through the hepatic artery against unresectable
liver metastases, and a high response rate has been
reported.9 –14 Recently, several trials of hepatic arterial
infusion (HAI) of fluoropyrimidines as adjuvant local
chemotherapy after curative hepatectomy have been
performed.15–25 However, to our knowledge few reports discussed its long term outcomes compared
with control treatment. It remains uncertain whether
HAI is beneficial in the prevention of recurrent disease. We investigated the efficacy of 5-fluorouracil
(5-FU) HAI as prophylactic regional chemotherapy after curative resection of colorectal liver metastases
using a prospective randomized study.
MATERIALS AND METHODS
From February 1993 to March 1995, 23 patients with
liver metastases from colorectal primary tumors underwent hepatic resection at Osaka National Hospital.
Of these patients, 19 age ⬍ 75 years with curative
resection and no serious preoperative complications
were entered into the study to evaluate HAI with 5-FU
as postoperative adjuvant chemotherapy after hepatectomy. Four patients were ineligible due to noncurative hepatectomy in 2 cases and age ⬎ 75 years in 2
cases. The protocol was approved by the Osaka National Hospital Institution Review Board.
Patients randomly were assigned treatment intraoperatively just after curative hepatectomy was performed. The randomization was performed by cards in
envelopes from a box that were supplied by an independent institute. There was no scheme of randomization. Each patient approved an informed consent
form prior to surgery. Nineteen patients were assigned
into an HAI group (9 patients) and a control group (10
patients).
Surgical Evaluation/Treatment
The liver metastases were removed either by anatomic
or nonanatomic hepatic resection according to the
tumor status (number, size, and location). In all patients, prophylactic cholecystectomy was performed
and intraoperative ultrasonography (US) was performed to confirm the status of the tumors, to identify
the exact anatomy of the liver in relation to the tumors, and to determine the transection line of hepatic
parenchyma. Surgery was considered curative when
all detectable tumors were removed with ⬎ 1 cm of
surgical margin. Pathologic examination also was performed to confirm the diagnosis and the negative surgical margin. In the HAI group, a catheter (Infuse-APort, Horizon Medical Products, Inc., Manchester, GA)
was inserted from the gastroduodenal artery and the
tip of the catheter was located at the junction of the
gastroduodenal artery and the hepatic artery. A port
connected to the catheter then was implanted subcutaneously in the right upper abdomen. In one case of
dual hepatic arterial supply, the right hepatic artery
arising from the superior mesenteric artery was ligated
and the catheter placed in the remaining artery. Adequacy of perfusion was confirmed intraoperatively
with infusion of diluted indigo carmine and postoperatively with enhanced computed tomography (CT)
through the port.
Chemotherapy
HAI was started on the fourteenth postoperative day
or when serum glutamic oxaloacetic transaminase (aspartate aminotransferase) fell to less than three times
normal. Two thousand milligrams of 5-FU diluted
with 20 mL of normal saline and 1000 u of heparin
were filled into a Baxter Infusor Multiday Type (Baxter
Healthcare Inc., Deerfield, IL) and infused at 0.5 mL/
hour (500 mg of 5-FU/day). Normally the chemotherapy was performed from Monday through Friday (96hour continuous infusion) followed by a 3-day rest,
which was defined as 1 cycle. The patients could go
about their daily lives in a nearly normal with the
external infusion pump because when filled with
agents the pump weighs as little as 125 g even on the
starting day. Six cycles of chemotherapy were administered to each patient. All treatment was performed
on an outpatient basis.
Treatment was held or discontinued for any toxicities greater than Grade 2 including hematologic,
gastrointestinal, neurologic, cutaneous, renal, and hepatic toxicities. Toxicities were classified using 1991/
1992 National Cancer Institute Common Toxicity Criteria (National Cancer Institute, Bethesda, MD).
The patients assigned to the control group received 200 mg/day of oral 5-FU from postoperative
Day 14 for 2 years. All patients who had completed
HAI also were administered the identical dose of oral
5-FU for the same period.
Follow-Up
All patients were followed at our institute and postoperative examinations were performed periodically according to the following schedule. Liver function tests
as well as blood cell counts were conducted every
week during HAI therapy and every 3 months in the
Adjuvant Regional Chemotherapy for Colorectal Liver Metatstases/Tono et al.
1551
TABLE 1
Patient Demographic Data
Age (mean ⫾ SD)
Gender (M/F)
Dukes Stage (B/C)
Tumor size (mm) (mean ⫾ SD)
Chronology (synchronous/metachronous)
No. of tumor (solitary/multiple)
Location (unilobar/bilobar)
Type of hepatectomy (anatomical/nonantomic)
HAI group (n ⴝ 9)
Control group (n ⴝ 10)
P value
59.0 ⫾ 5.8
5/4
2/7
26.3 ⫾ 14.9
4/5
3/6
5/4
5/4
61.9 ⫾ 5.0
6/4
3/7
19.3 ⫾ 8.6
6/4
7/3
8/2
4/6
0.0887
0.8447
⬎ 0.9999
0.2189
0.8087
0.1547
0.4988
⬎ 0.9999
HAI: hepatic arterial infusion; SD: standard deviation; M: male; F: female.
later course. Tumor markers including carcinoembryonic antigen and carbohydrate antigen 19-9 were
measured every 3 months. Hepatic US and/or CT scan
were performed every 3 months up to 2 years after
hepatectomy and every 6 months thereafter. Chest
X-ray films were examined every 6 months and chest
CT scan was performed once a year. Pelvic or abdominal CT scans also were examined periodically in patients with locally advanced disease.
Statistical Analysis
The survival curve was obtained by the Kaplan–Meier
method and comparisons between groups were performed by the log rank test. The distribution of patient
characteristics in the two groups was examined by the
chi-square test. The comparison of the mean value
was performed by the Student t test. The level of
statistical significance was P ⬍ 0.05.
RESULTS
Patient Characteristics
There were five males and four females in the HAI
group and six males and four females in the control
group (Table 1). The mean ages in each group were
59.0 ⫾ 5.8 years (mean ⫾ standard deviation) and
61.9 ⫾ 5.0 years, respectively. In terms of Dukes Stage
for the original carcinoma, two of nine cases were
Stage B and the remaining seven were Stage C in the
HAI group, whereas three of ten cases were Stage B
and seven were Stage C in the control group. The
average greatest tumor dimension in the HAI group
was 26.3 ⫾ 14.9 mm, and that of the control group was
19.3 ⫾ 8.6 mm. Synchronous metastases were found
in 44.4% of the patients in the HAI group and 60.0% of
the patients in the control group. Three patients in the
HAI group had solitary tumors whereas seven of ten
patients in the control group had a single metastasis in
the liver. In the HAI group, metastatic lesions were
observed in a unilateral lobe of the liver in five pa-
tients and in bilateral lobes in four patients. In the
control group, eight patients had unilobar tumors and
two had bilobar lesions. With regard to surgical procedures, anatomic hepatic resection was performed in
55.6% of the patients in the HAI group and nonanatomic (wedge) resection was performed in the remaining 44.4% of patients. Conversely, in the control group,
40.0% of patients underwent anatomic resection and
the remaining 60.0% underwent nonanatomic hepatectomy.
None of these findings were regarded as statistically significant between the two groups.
Toxicity
Only one patient of nine who received regional chemotherapy developed Grade 1 nausea and anorexia,
which were endurable. No patients had hematologic
toxicity, hepatitis, sclerosing cholangitis, or complications related to the implantable port system. Thus all
nine patients were completely able to receive HAI
chemotherapy for 6 weeks on schedule. Based on hepatic CT scans examined 3 months after surgery, HAI
chemotherapy did not affect the regenerative capacity
of the residual liver. There were no apparent adverse
effects with regard to the oral administration of 5-FU.
Recurrence of Disease
All 19 patients enrolled in the current study were
evaluable. The range of follow-up was between 49.5–
70.0 months, and the median follow-up was 62.2
months. Disease recurrence was observed in 8 patients (80.0%) in the control group and in 3 patients
(33.3%) in the HAI group. Six of eight patients in the
control group who developed disease recurrence had
recurrent tumors in the residual liver, whereas one
patient of three in the HAI group was found to have
recurrent lesions in the liver.
Among five patients in the control group who had
recurrent tumors only in the liver, three underwent a
1552
CANCER April 1, 2000 / Volume 88 / Number 7
FIGURE 1.
Disease free survival after hepatectomy. Solid line: hepatic
arterial infusion group (n ⫽ 9); dashed line: control group (n ⫽ 10).
FIGURE 2. Cumulative survival after hepatectomy. Solid line: hepatic arterial
infusion group (n ⫽ 9); dashed line: control group (n ⫽ 10).
second hepatectomy. The remaining two patients and
one patient with both intrahepatic and extrahepatic
disease received regional chemotherapy. The other
two patients with extrahepatic recurrence in the control group received systemic chemotherapy. Conversely, of the three patients with recurrent disease in
the HAI group, one underwent a repeat hepatectomy,
one underwent resection of lung metastases, and the
remaining patient received systemic chemotherapy.
plained from the concepts of “first pass effect” and
“increased local concentration.”26 Because fluoropyrimidines have high rate of first-pass hepatic extraction,
a high concentration of the drug in the liver with
limited systemic exposure is obtained with HAI of
fluoropyrimidines.26 –28 The advantage of hepatic arterial delivery of fluoropyrimidines also is understood
from its increased local concentration without the
first-pass effect calculated from the ratio of total body
clearance of the drug.29 Colorectal liver metastases
derive their blood supply almost exclusively from the
hepatic artery, whereas normal hepatic parenchyma is
perfused both by the portal vein and the hepatic artery.30 These findings encourage physicians to perform HAI chemotherapy with fluoropyrimidines for
the treatment of liver metastases from colorectal primary tumors.
Several significant attempts to use HAI as adjuvant chemotherapy after hepatectomy have been performed and a decreased disease recurrence rate in the
remnant liver has been reported (Table 2).15–23 However, the majority of the studies did not include the
appropriate control treatment or the follow-up period
was not long enough to evaluate the efficacy of prophylactic regional chemotherapy. Thus our prospective randomized study was designed to determine
whether HAI chemotherapy after curative resection of
colorectal liver metastases is beneficial. Our trial, with
⬎ 5 years of observation, revealed that the disease free
survival of patients who received HAI was significantly
higher than that of the control group (P ⫽ 0.045). This
result is consistent with two previous reports of randomized trials of adjuvant HAI chemotherapy, although the number of patients or the length of the
follow-up period did not appear ideal in those stud-
Survival
The median disease free interval after hepatectomy
was 62.6 months (range, 5.1–70 months) in the HAI
group and 13.8 months (range, 4.5– 60.5 months) in
the control group. The 1-, 2-, and 3-year disease free
survival rates in the control group were 50.0%, 30.0%,
and 20.0%, respectively, whereas those of the HAI
group were 77.8%, 77.8%, and 66.7%, respectively (Fig.
1). The difference between the groups was regarded as
statistically significant (P ⫽ 0.045).
Two patients in the HAI group and five patients in
the control group were dead of disease at last followup. The median survival time of the HAI group was
62.6 months (range, 11.2–70.0 months) and that of the
control group was 39.9 months (range, 20.4 – 60.5
months). The 1-, 3-, and 5-year cumulative survival
rates in the HAI group were 88.9%, 77.8%, and 77.8%,
respectively, and 100.0%, 50.0%, and 50.0%, respectively, in the control group (Fig. 2). No significant
difference was found between the cumulative survival
of the two treatment groups (P ⫽ 0.2686).
DISCUSSION
The advantage of local arterial chemotherapy compared with systemic therapy is pharmacologically ex-
Adjuvant Regional Chemotherapy for Colorectal Liver Metatstases/Tono et al.
1553
TABLE 2
Reported Studies of Prophylactic HAI Chemotherapy after Curative Resection of Colorectal Carcinoma Metastatic to the Liver
Authors
Year
No. of
patients
Device
Agents
Period
of HAI
Control
Outcomes
Complications
Patt et al.15
1987
20
NP
FUDR, MMC
16 weeks
No
MST: 51 mos, LR: 35%
Wagman et al.16
1990
11
IP
FUDR
12 mos
Rand
Moriya et al.17
Curley et al.18
Kemeney et al.19
Lygidakis et al.20
Okuno et al.21
Nonami et al.22
Lorenz et al.23
Current series
1991
1993
1993
1995
1996
1997
1998
16
18
8
38
18
31
226
19
EP
EP
IP
IP
EP
EP
EP
EP
5-FU, MMC, oral HCFU
5-FU
FUDR, iv 5-FU, iv LV
5-FU, MMC, ␣IFN, IL-2 etc.
5-FU, MMC, IL-2
5-FU, MMC, ADM
5-FU, FA
5-FU
6 mos
6 mos
6 mos
3 yrs
6 mos
12 mos
6 mos
6 weeks
No
No
No
Rand
Hist
Hist
Rand
Rand
MDFST: 30.7 mos vs. 8.7 mos (P ⫽
0.03)
LR: 31%
MST: 33 mos, LR: 17%
MST: 23 mos, LR: 0%
MST: 20 mos vs. 11 mos (P ⬍ 0.001)
MST: 36.5 mos, LR: 0% vs. 50%
5-yr SR: 57% vs. 10% (P ⬍ 0.05)
MDFST: 21.6 mos vs. 24 mosa
5-yr DFSR: 66.7% vs. 20% (P ⫽ 0.045)
Hepatitis: 70%, peptic ulcer:
23%
Dead of complications: 40%
Hepatitis: 19%, cholangitis: 19%
Cessation of HAI: 44%
Hepatitis: 50%
Granulopenia 16%, fever 100%
Cholangitis: 6%, fever 100%
Peptic ulcer: 3%
30-day death: 7.5%
None
HAI: hepatic arterial infusion; NP: no port implanted; FUDR: floxuridine; Rand: randomized study; MMC: mitomycin C; MST: median survival time; LR: liver recurrence rate; IP: implanted pump; MDFST: median
disease free survival time; EP: external pump with implanted port; 5-FU: 5-fluorouracil; HCFU: 1-hexycarbamoyl-5-fluorouracil; iv: intravenous; LV: leucovorin; ␣IFN: ␣-interferon; IL-2; interleukin 2; Hist: historic
control; ADM: doxorubicin; SR: survival rate; FA: folinic acid; DFSR: disease free survival rate.
a
Depends on the subject of each analysis; data will be altered to 44.8 mos versus 23.3 mos.
ies.16,20 Recently Lorenz et al. reported that a decreased recurrence rate was not obtained with postoperative adjuvant HAI therapy in a randomized trial
with large number of patients.23 However, in the study
only 74% of the patients assigned to the HAI group
received the therapy. The median disease free survival
time was nearly doubled (44.8 months vs. 23.3
months) when analysis was performed in patients actually treated. It has been reported that several prognostic factors such as Dukes stage, tumor size, chronology, the number of tumors, and others may relate
to the outcome after curative hepatectomy of metastatic colorectal carcinoma.1–5 It might be difficult to
deny that some differences in patient background factors between the HAI and control groups in the current series could have affected the outcome of the
randomized trial because the number of patients entered is relatively small. However, no significant difference was observed between the two groups, and the
majority of those factors were even favorable in the
control group, which showed a lower survival rate
(Table 1).
In terms of the duration of adjuvant regional chemotherapy, many investigators continued HAI for ⱖ 6
months after hepatectomy.16 –23 The period of prophylactic HAI in the current trial was only 6 weeks and the
total dosage of 5-FU administered intraarterially was
as low as 12 g. Some may ask whether such an amount
of 5-FU could be potent enough to suppress recurrence of the disease. However, the majority of hepatic
recurrences after curative resection of liver metastases
arise from subclinical or microscopic lesions in the
remnant liver, which are the targets of adjuvant HAI
therapy. There is a report that regional infusion of an
amount of 5-FU similar to that used in the current
decreased the recurrence rate compared with the historic control.31
It is known that the hepatic extraction rate of
floxuridine (FUDR) is higher than 5-FU, and FUDR has
been regarded as the best drug for HAI chemotherapy.32 However, 5-FU still is pharmacologically superior to agents other than fluoropyrimidines for HAI
therapy.26,28,29 Several reports have demonstrated that
HAI of 5-FU in patients with unresectable liver metastases showed a response rate of 50 –75%,33–35 which is
similar to the result observed with HAI using
FUDR.9 –14
A major problem of HAI chemotherapy is the high
rate of incidence of toxicities and complications related to the therapy. Kemeney reported that 6 –25% of
patients with unresectable metastases who received
HAI of FUDR developed serious hepatobiliary toxicities such as sclerosing cholangitis, which often is fatal.36 Frequent hepatobiliary toxicity also was observed in patients treated with prophylactic HAI of
FUDR.15,16,19 Wagman et al. reported two of five patients treated with prophylactic HAI of FUDR died of
hepatobiliary toxicities,16 which appears to be an unacceptable event because the patients had received
adjuvant therapy after curative surgery. In contrast,
5-FU is recognized as less toxic, especially to the hepatobiliary tract,37,38 and low levels of toxicities were
reported in patients treated with prophylactic HAI of
5-FU.18,21,22 In the current series only one patient reported Grade 1 gastrointestinal symptoms, and no
1554
CANCER April 1, 2000 / Volume 88 / Number 7
other adverse effects were observed throughout the
therapy.
Conversely, some reports pointed out that HAI of
5-FU often resulted in arteritis or hepatic arterial
thrombosis.35,36,39 Curley et al. reported that arteritis,
arterial thrombosis, and irreversible port or catheter
occlusion occurred in 2, 1, and 3 patients, respectively,
of 18 patients who received adjuvant HAI (10-minute
injection) of 5-FU for 24 weeks, and chemotherapy
had to be discontinued in those instances.18 In the
current study there was no apparent complication in 9
patients who received 24-hour infusion of 5-FU for 6
weeks with 4 days of administration and 3 days of rest.
Of course we cannot ignore the possibility of subclinical events such as hepatic arterial stenosis, because
detailed examinations including angiography were not
performed after termination of HAI. However, liver
function tests remained normal throughout the therapy period, and no patients reported fever or abdominal pain. We speculate the reason why no serious
complication was observed in the current trial was
due simply to the short duration of infusion therapy.
There might be an opinion that the device used in
this study, an implanted small port with external infusion pump, is suboptimal. Indeed the totally implantable pump used by many researchers has many
beneficial aspects.40,41 However, the device is very expensive and removal of the whole system is nearly
impossible. In our protocol, the patients could maintain a fairly satisfactory quality of daily life because the
external pump used was very small and lightweight.
The period of chemotherapy was so short (6 weeks)
that few patients complained about the inconvenience
related to the treatment. Furthermore, in recent patients receiving prophylactic regional chemotherapy,
we have placed a catheter by a percutaneous method
through the femoral or subclavian artery.42 Thus the
catheter as well as the port can be removed easily
whenever adjuvant chemotherapy is completed and
no further treatment is regarded as needed.
It is not surprising that there was no significant
difference in the cumulative survival rate between the
HAI and control groups despite the disease free survival being significantly higher in the HAI group. First,
the significance of aggressive surgical treatment including repeated hepatectomy for recurrent disease
after first resection of colorectal liver metastases has
been well established.43– 45 Four patients with recurrent hepatic lesions in the current study underwent
second resection of the liver, which could affect the
outcome of overall survival. Furthermore, the existence of extrahepatic disease recurrence also plays a
critical role in determining the result after curative
resection of liver metastases from colorectal primary
tumors. Thus development of effective combined protocols of HAI and systemic chemotherapy is required
if physicians wish to obtain a survival benefit from
adjuvant chemotherapy after curative hepatectomy of
colorectal liver metastases.
From the viewpoint of prophylactic chemotherapy, approaches different from the treatment of patients with unresectable metastases are needed.
Nearly 50% of the patients who undergo curative resection of colorectal liver metastases have no further
disease, at least in the remnant liver.1–5 Therefore, we
need to adopt a treatment regimen with a minimal
possibility of serious adverse effects. Patients should
be released from the hospital and free from intensive
treatment at an early phase after surgery.
Despite the fact that no survival benefit was confirmed, significantly improved disease free survival
was obtained by 6 weeks with HAI of 5-FU after curative resection of colorectal liver metastases in this
randomized study. Thus we conclude that short term
HAI of 5-FU as adjuvant chemotherapy can result in
patients who undergo curative hepatectomy having a
higher disease free survival and a decreased possibility
of additional surgical treatment for recurrent disease
without any serious complications. Further studies
with larger number of patients are required to confirm
the result of the current study. Multiinstitutional randomized trials of adjuvant HAI of 5-FU using an external pump in ⬎ 100 patients currently are in
progress and preliminary analysis suggests that effectiveness similar to the current study was obtained by
HAI of 5-FU (Mori T, personal communication).
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