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Hiyama et al. Hepatoma Res 2021;7:44 https://dx.doi.org/10.20517/2394-5079.2021.21 Page 3 of 12

resection and were excluded. Then, we analyzed the local recurrence and survival rates of the remaining 337
patients who underwent hepatic tumor resection including total hepatectomy with living-donor LT. In these
cases, 14 PRETEXT I and 16 PRETEXT II cases underwent initial resection at diagnosis and 10 additional
cases (4 PRETEXT I and 6 PRETEXT II) with tumor rupture also underwent initial resection at diagnosis
for control of intra-abdominal hemorrhage.

Ethics approval was obtained from the ethics committee of each institution (Hiro-I-RIN-118). Written
informed consent was obtained from the patients and/or parents before treatment.

Staging and treatments
A physical examination with medical history was carefully taken and routine imaging studies including
chest radiography, abdominal ultrasound, contrast-enhanced computed tomography (CT), and magnetic
resonance imaging (MRI) were performed according to the guideline of the JPLT-2 protocol. Blood samples
were collected for liver function tests and alpha-fetoprotein (AFP) measurement according to the JPLT- 2
protocol.

Clinical staging was performed institutionally according to PRETEXT criteria as defined by SIOPEL [20,21] .
[22]
PRETEXT annotation factors were defined according to the 2005 revised PRETEXT criteria . In this study,
23 tumors were classified as PRETEXT I, 120 as PRETEXT II, 134 as PRETEXT III, and 84 as PRETEXT IV.
We reclassified tumor histology according to an international pediatric liver consensus classification
system .
[23]
The JPLT-2 protocol was designed to confirm the effectiveness of pre- and postoperative CTx. In JPLT-2,
preoperative CTx using the cisplatin-pirarubicin (tetrahydropyranyl-adriamycin) regimen (CITA) and the
second-line regimen of ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC) were administered
according to the PRETEXT-based risk stratification system [Figure 1] [3,19] . For patients with unresectable or
metastatic disease, we evaluated the efficacy of high-dose CTx with stem cell transplantation [3,24-26] . Briefly,
PRETEXT I tumors and some PRETEXT II tumors without PRETEXT annotation factors were resected at
diagnosis (up-front resection) (Stratum 1). Ruptured PRETEXT I or II tumors also underwent up-front
resection to control hemorrhaging. PRETEXT II tumors without annotation factors, except for tumor
multifocality, received two cycles of preoperative CTx with half-dose CITA (Stratum 2). All PRETEXT III or
IV and PRETEXT I/II tumors with annotation factors, including preoperative rupture without initial
resection, macrovascular invasion, and metastatic disease, received two cycles of preoperative CITA.
Patients who were deemed responders, according to the RECIST criteria and a decreased AFP level,
underwent two more cycles of CITA followed by resection (Stratum 3). For non-responders, two cycles of
the ITEC regimen were added (Stratum 4). CITA or ITEC was repeated for six cycles if surgical treatment
was considered difficult after four cycles. All patients in the whole cohort received postoperative CTx.
Patients in Stratum 1 or 2 were treated with two cycles of low-dose CITA, and those in Stratum 3 or 4 were
treated with two cycles of CITA or ITEC, respectively. If no complete response of the metastatic lesions was
achieved at this point, two additional cycles were added. Patients with persistent metastatic disease or
refractory PRETEXT IV disease were eligible to receive high-dose CTx with stem cell transplantation after
tumor resection (including metastasectomy) according to the institutional decision.

Determination of a positive margin
The histopathologic classification of the specimens at diagnosis was performed via central review by three
pathologists [Figure 2]. The diagnosis of microMPR and microMNR (complete resection) was based on
local pathology reports; the diagnosis of some cases was determined by central review.