Publications by authors named "Tomoro Hishiki"

59 Publications

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants.

N Engl J Med 2021 01;384(1):42-50

From the Departments of Pediatric Oncology (A.A., T. Kumamoto, M.N., C.O.), Laboratory Medicine (T. Kubo, K. Sunami, H.K.), Diagnostic Pathology (N.M., H.Y.), Breast and Medical Oncology (K. Yonemori, E.N.), Pediatric Surgical Oncology (T.H., N.K.), and Experimental Therapeutics (N. Yamamoto), National Cancer Center Hospital, the Departments of Clinical Genomics (H.I., T. Kubo) and Immune Medicine (K.A.), and the Divisions of Genome Biology (K. Shiraishi, T. Kohno), Cancer Genomics (Y.A., T.S.), and Cancer Immunology (Y.T., H.N.), National Cancer Center Research Institute, the Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center (H.I., T. Kubo, T. Kohno), the Children's Cancer Center, National Center for Child Health and Development (T.H.), the Departments of Obstetrics and Gynecology (T. Kuroda, K. Yamada, N. Yanaihara, K. Takahashi, A.O.) and Pathology (T. Kiyokawa), Jikei University School of Medicine, the Departments of Pediatrics (S.H., D.H., A.M.) and Integrated Women's Health (K.O.), St. Luke's International Hospital, and the Department of Pediatrics, Toho University School of Medicine (M.M.), Tokyo, and the Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo (S.H., A.M.) - both in Japan.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).
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http://dx.doi.org/10.1056/NEJMoa2030391DOI Listing
January 2021

Optimization of surgical timing of congenital diaphragmatic hernia using the quantified flow patterns of patent ductus arteriosus.

Pediatr Surg Int 2021 Feb 3;37(2):197-203. Epub 2021 Jan 3.

Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Purpose: The optimal timing of surgery for congenital diaphragmatic hernia (CDH) is controversial. We aimed to validate our protocol for the timing of CDH repair using the quantified patent ductus arteriosus (PDA) flow pattern.

Methods: This retrospective comparative study analyzed patients with a prenatal diagnosis of isolated CDH between 2007 and 2020. We defined the "LR ratio" as the percentage of velocity-time integral (VTI) of the left-to-right flow of PDA against overall VTI on echocardiography. Since 2010, we followed the decision criterion of performing surgery when LR ratio of > 50% has been achieved in the patients (protocol group). The protocol group (2010-2020) was compared with the historical control group (2007-2009).

Results: The average age at surgery was 104.1 ± 175.9 and 37.3 ± 30.6 h in the control and protocol groups, respectively (p = 0.11). Survival rate (88.9% vs. 95.0%, p = 0.53) and the rate of worsening of pulmonary hypertension within 24 h after surgery (22.2% vs. 10.0%, p = 0.57) were not different between the groups. The protocol group had a significantly shorter duration of tracheal intubation (26.9 ± 21.1 vs. 13.3 ± 9.5 days, p = 0.03).

Conclusion: Our decision criterion might have the advantage of facilitating early and safe surgery for patients with CDH.
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http://dx.doi.org/10.1007/s00383-020-04788-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778689PMC
February 2021

Sindbis viral structural protein cytotoxicity on human neuroblastoma cells.

Pediatr Surg Int 2020 Oct 21;36(10):1173-1180. Epub 2020 Jul 21.

Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan.

Purpose: Oncolytic viral therapy for neuroblastoma (NB) cells with Sindbis virus (SINV) is a promising strategy for treating high-risk NB. Here, we evaluated the possibility of using SINV structural proteins as therapeutic agents for NB since UV-inactivated SINV could induce cytopathogenic effects.

Methods: The cytotoxicity of UV-inactivated SINV toward human NB cell lines NB69, NGP, GOTO, NLF, SK-N-SH, SH-SY5Y, CHP134, NB-1, IMR32, and RT-BM-1 were analyzed. Apoptosis was confirmed by TUNEL assays. To determine the components of SINV responsible for the cytotoxicity of UV-inactivated SINV, expression vectors encoding the structural proteins, namely capsid, E2, and E1, were transfected in NB cells. Cytotoxicity was evaluated by MTT assays.

Results: UV-inactivated SINV elicited more significant cytotoxicity in NB69, NGP, and RT-BM-1 than in normal human fibroblasts. Results of the transfection experiments showed that all NB cell lines susceptible to UV-inactivated SINV were highly susceptible to the E1 protein, whereas fibroblasts transfected with vectors harboring capsid, E1, or E2 were not.

Conclusions: We demonstrated that the cytotoxicity of the UV-inactivated SINV is due to apoptosis induced by the E1 structural protein of SINV, which can be used selectively as a therapeutic agent for NB.
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http://dx.doi.org/10.1007/s00383-020-04719-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474708PMC
October 2020

Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

J Clin Oncol 2020 08 18;38(22):2488-2498. Epub 2020 May 18.

Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan.

Purpose: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB).

Patients And Methods: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease.

Results: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis.

Conclusion: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.
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http://dx.doi.org/10.1200/JCO.19.01067DOI Listing
August 2020

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

Pediatr Blood Cancer 2020 08 8;67(8):e28350. Epub 2020 May 8.

Division of Pediatric Surgery, University of Utah School of Medicine, Utah, Salt Lake City.

Purpose: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification.

Methods: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors.

Results: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture.

Conclusion: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.
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http://dx.doi.org/10.1002/pbc.28350DOI Listing
August 2020

High prevalence of SMARCB1 constitutional abnormalities including mosaicism in malignant rhabdoid tumors.

Eur J Hum Genet 2020 08 26;28(8):1124-1128. Epub 2020 Mar 26.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

Intensive analysis of the SMARCB1 gene in malignant rhabdoid tumors (MRT) revealed eight of 16 patients with constitutional genetic variants. Three patients had mosaicism of deletion/variant of the SMARCB1 gene, which conventional methods might overlook. The prevalence of cancer predisposition in MRT may thus be higher than previously reported.
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http://dx.doi.org/10.1038/s41431-020-0614-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381660PMC
August 2020

Definitive Tumor Resection after Myeloablative High Dose Chemotherapy Is a Feasible and Effective Option in the Multimodal Treatment of High-Risk Neuroblastoma: A Single Institution Experience.

J Pediatr Surg 2020 Aug 4;55(8):1655-1659. Epub 2019 Sep 4.

Division of Surgery, Department of Surgical Specialties, National Center for Child Health and Development.

Background/purpose: The delayed local treatment approach (DL) in high-risk neuroblastoma (HR-NB) refers to the process in which tumor resection is performed after the completion of all the courses of chemotherapy, including myeloablative high-dose chemotherapy (HDC). Alternatively, in the conventional local treatment approach (CL), tumor resection is performed during induction chemotherapy. In this study, we compared the surgical outcomes in HR-NB patients treated by CL and DL.

Method: Forty-seven patients with abdominal HR-NB underwent primary tumor resection from 2002 to 2018. The timing of surgery was generally determined by following the trials and guidelines available at the time. The outcomes and surgical complications between the two strategies were compared.

Result: Operation time, blood loss, and postoperative WBC counts were lower in the DL group (n = 25) when compared to the CL group (n = 22), statistical significance notwithstanding. Major vascular structures were less frequently encased in the DL group tumors, while immediate surgical complications were significantly more frequent in the CL group (P < 0.05). Furthermore, the 3-year EFSs were 50.0% and 53.9% in the DL and CL groups, respectively.

Conclusion: DL appears to be a feasible and effective treatment option for HR-NB. Nonetheless, further verifications using larger cohorts are warranted.

Level Of Evidence: Treatment study, Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.08.050DOI Listing
August 2020

Fluorescence-Guided Surgery for Hepatoblastoma with Indocyanine Green.

Cancers (Basel) 2019 Aug 20;11(8). Epub 2019 Aug 20.

Division of Surgical Oncology, National Center for Child Health and Development, Tokyo 157-0074, Japan.

Fluorescence-guided surgery with indocyanine green (ICG) for malignant hepatic tumors has been gaining more attention with technical advancements. Since hepatoblastomas (HBs) possess similar features to hepatocellular carcinoma, fluorescence-guided surgery can be used for HBs, as aggressive surgical resection, even for distant metastases of HBs, often contributes positively to R0 (complete) resection and subsequent patient survival. Despite a few caveats, fluorescence-guided surgery allows for the more sensitive identification of lesions that may go undetected by conventional imaging or be invisible macroscopically. This leads to precise resection of distant metastatic tumors as well as primary liver tumors.
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http://dx.doi.org/10.3390/cancers11081215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721588PMC
August 2019

Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation.

Cancer Sci 2019 Mar 1;110(3):888-902. Epub 2019 Feb 1.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.
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http://dx.doi.org/10.1111/cas.13933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398884PMC
March 2019

An investigation on clinical differences between congenital pulmonary airway malformation and bronchial atresia.

J Pediatr Surg 2018 Dec 1;53(12):2390-2393. Epub 2018 Sep 1.

Division of Surgery, National Center for Child Health and Development, Tokyo, Japan.

Background/purpose: Differences in clinical features between congenital pulmonary airway malformation (CPAM) and bronchial atresia (BA) have not yet been clearly described.

Methods: We retrospectively reviewed 112 patients with a pathological diagnosis of CPAM or BA. The clinical parameters were statistically analyzed between these diseases.

Results: Seventy-one patients received prenatal diagnosis and 41 received postnatal diagnosis. The percentage of prenatal diagnosis was significantly higher in CPAM patients (84% vs 50%, p < 0.001). Among patients with prenatal diagnosis, the backgrounds were not different between the two diseases except for the number of Caesarean sections (81% vs 9%, p < 0.0001). The numbers of patients that underwent fetal interventions and emergent neonatal surgery were higher in CPAM (51% vs 15%, p < 0.01 and 76% vs 12%, p < 0.0001), although there was no statistical difference in survival rate (86% vs 97%, p = 0.2). In patients receiving postnatal diagnosis, pneumonia was the primary symptom in most BA patients, whereas respiratory distress was the major symptom in patients with CPAM. Age at presentation of the primary symptom was significantly older in BA patients (4.2 years vs 1.2 years, p < 0.005).

Conclusion: CPAM and BA have distinct clinical features in terms of therapeutic and natural history. Careful imaging evaluation and pathological analysis can lead to an accurate diagnosis of BA.

Type Of Study: Prognostic study.

Level Of Evidence: Level II. This study is categorized as a "Prognostic Study" with LEVEL III of Evidence.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.08.031DOI Listing
December 2018

Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA.

Genes Chromosomes Cancer 2018 10 20;57(10):525-529. Epub 2018 Aug 20.

Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.

Clear cell sarcoma of the kidney (CCSK) is the second most common renal malignancy in children. The prognosis is poorer in CCSK than in Wilms' tumor, and multimodal treatment including surgery, intensive chemotherapy, and radiation is required to improve the outcome for children with CCSK. Histological evaluation is required for the diagnosis. However, biopsies of tumors to obtain diagnostic specimens are not routinely performed because of the risk of spreading tumor cells during the procedure. Recently, internal tandem duplication (ITD) of BCOR has been recognized as a genetic hallmark of CCSK. We herein established a novel BCOR-ITD-specific polymerase chain reaction method with well-designed primers, and then performed a liquid biopsy for cell-free DNA (cfDNA) obtained from plasma of three children with nonmetastatic renal tumors (stage II) and from one control. BCOR-ITD was positively detected in the cfDNA of two cases, both of which were later diagnosed as CCSK based on histological feature of the resected tumor specimen, while it was not detected for a normal control and a patient diagnosed with Wilms' tumor. Our study is the first one of preoperative circulating tumor DNA assay in pediatric renal tumors. The liquid biopsy method enables less invasive, preoperative diagnosis of CCSK with no risk of tumor spillage, which can avoid iatrogenic upstaging.
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http://dx.doi.org/10.1002/gcc.22648DOI Listing
October 2018

Surgical treatment strategy for advanced hepatoblastoma: Resection versus transplantation.

Pediatr Blood Cancer 2018 12 7;65(12):e27383. Epub 2018 Aug 7.

Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

Background: Excellent outcomes of the extreme procedure of liver resection (LR) for advanced hepatoblastoma (HB) have been achieved in recent reports. However, liver transplantation (LT) remains the only surgical treatment for patients with unresectable HB. The aim of this study was to evaluate our retrospective data for cases of advanced HB necessitating surgical intervention and analyze the prognostic factors of recurrence by comparing patients with tumors resected by LR and LT.

Patients And Methods: We retrospectively reviewed 24 children with PRETEXT II/III/IV tumors that required consideration for LT between August 2011 and September 2016.

Result: The staging at the time of the diagnosis was PRETEXT II/III/IV in 1/13/10 patients, respectively, while the preoperative staging after neoadjuvant chemotherapy was POSTTEXT II/III/IV in 5/17/2 patients. Among those 24 patients, complete resection of the primary tumor was achieved with LT in 12 patients and LR in 12 patients. A high serum level of alpha-fetoprotein (AFP) at the time of surgery, no significant decrease in the rate of change of AFP, and low tumor shrinkage rate were related to the risk of tumor recurrence, and patients with tumors resected by LR with those risks had a higher recurrence rate than those without them. The overall survival was higher in patients with tumors resected by LT (100%) than in patients with tumors resected by LR.

Conclusion: Patients with advanced HB with a poor response to chemotherapy should definitively be prioritized for primary LT, given the possibility of vascular invasion and microscopic residual tumor.
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http://dx.doi.org/10.1002/pbc.27383DOI Listing
December 2018

Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG).

Int J Clin Oncol 2018 Oct 26;23(5):965-973. Epub 2018 Apr 26.

Saga Medical Center KOSEIKAN Hospital, Saga, Japan.

Background: The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies.

Methods: JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy.

Results: The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 ± 7.0 and 69.5 ± 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification.

Conclusions: The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort.
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http://dx.doi.org/10.1007/s10147-018-1281-8DOI Listing
October 2018

Modified triangular hepatic vein reconstruction for preventing hepatic venous outflow obstruction in pediatric living donor liver transplantation using left lateral segment grafts.

Pediatr Transplant 2018 05 1;22(3):e13167. Epub 2018 Apr 1.

Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

HVOO can be a critical complication in pediatric LDLT. The aim of this study was to evaluate a modified triangular technique of hepatic vein reconstruction for preventing HVOO in pediatric LDLT. A total of 298 pediatric LDLTs were performed using a left lateral segment graft by 2 methods for reconstruction of the hepatic vein. In 177 recipients, slit-shaped anastomosis was indicated with partial clamp of the IVC. A total of 121 recipients subjected to the modified triangular anastomosis with total clamp of the IVC. We compared the incidence of hepatic vein anastomotic complications between these 2 methods. Nine of the 177 cases (5.3%) treated with the conventional technique were diagnosed with outflow obstruction. All 9 cases underwent hepatic vein reconstruction with the slit-shaped hepatic vein anastomosis. In contrast, there were no cases of outflow obstruction in the 121 cases treated with the modified triangular anastomosis. The modified triangular technique of hepatic vein reconstruction with total clamping of the IVC was useful for preventing HVOO in pediatric LDLT.
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http://dx.doi.org/10.1111/petr.13167DOI Listing
May 2018

Ex vivo reduction of thickness in the left lateral section to tailor the graft size in infantile split deceased donor liver transplantation.

Liver Transpl 2018 03 12;24(3):428-431. Epub 2018 Feb 12.

Organ Transplantation Center National Center for Child Health and Development, Tokyo, Japan.

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http://dx.doi.org/10.1002/lt.24976DOI Listing
March 2018

Invariant natural killer T infiltration in neuroblastoma with favorable outcome.

Pediatr Surg Int 2018 Feb 10;34(2):195-201. Epub 2017 Oct 10.

Department of Medical Immunology, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics.

Methods: Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients' outcome.

Results: Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089).

Conclusions: Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.
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http://dx.doi.org/10.1007/s00383-017-4189-xDOI Listing
February 2018

Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with malignant solid tumors.

Pediatr Surg Int 2018 Feb 10;34(2):169-176. Epub 2017 Oct 10.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Invariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer.

Methods: Blood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed.

Results: The frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro.

Conclusions: Unlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.
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http://dx.doi.org/10.1007/s00383-017-4185-1DOI Listing
February 2018

The role of pulmonary metastasectomy for hepatoblastoma in children with metastasis at diagnosis: Results from the JPLT-2 study.

J Pediatr Surg 2017 Dec 4;52(12):2051-2055. Epub 2017 Sep 4.

Japan Children's Cancer Group (JCCG) liver tumor committee (JPLT).

Background/purpose: The purpose of this study was to clarify the role of pulmonary metastasectomy in hepatoblastomas with lung metastasis at diagnosis. We reviewed cases enrolled in the JPLT-2 study.

Methods: A total of 360 cases with hepatoblastoma were enrolled. The clinical courses and outcome of 60 cases with pulmonary metastasis at diagnosis were reviewed, focusing on metastasectomy.

Results: Induction chemotherapy resulted in eradication of nodules in 26, residual nodules in 33, and early treatment-related death in one. Of the 33 cases with residual nodules, 11 underwent complete resection of the lung lesions, and among these, progression was reported in five. Complete resection of the liver tumor was not achieved in two of these. Three underwent incomplete resection of lung nodules, eventually leading to progression. Twelve cases with incomplete or no liver tumor resection progressed regardless of the status of lung lesions. Contrarily, among patients who underwent complete resection of the liver tumor, half were cured without metastasectomy.

Conclusions: Metastasectomy for residual pulmonary nodules after induction chemotherapy is effective provided that the liver tumor could be completely resected.

Type Of Study: Prospective Cohort Study.

Level Of Evidence: Level II.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.08.031DOI Listing
December 2017

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.

Lancet Oncol 2017 01 22;18(1):122-131. Epub 2016 Nov 22.

Medical University of Gdansk, Gdansk, Poland.

Background: Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer.

Methods: The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system.

Results: Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high.

Interpretation: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT).

Funding: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.
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http://dx.doi.org/10.1016/S1470-2045(16)30598-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650231PMC
January 2017

Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol.

J Pediatr Surg 2016 Dec 17;51(12):2053-2057. Epub 2016 Sep 17.

Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, 734-8551, Japan.

Background/purpose: We aimed to clarify whether surgical resectability and tumor response after preoperative chemotherapy (preCTx) represented prognostic factors for patients with hepatoblastoma (HBL) in the JPLT-2 study (1999-2012).

Methods: Patients (N=342) with HBL who underwent preCTx were eligible. PRETEXT, CHIC risk stratification (standard [SR], intermediate [IR] and high risk [HR]) at diagnosis, POST-TEXT, and tumor resectability were evaluated by imaging. Tumor response was classified into responders (CR or PR) and nonresponders (NC or PD) according to RECIST criteria.

Results: There were 7 PRETEXT I, 106 II, 143 III, and 86 IV, including 71 metastatic HBLs. In POST-TEXT, 12 PRETEXT II, 42 III, and 58 IV were down-staged. The 5-year EFS/OS rates of 198 SR, 73 IR, and 71 HR-HBLs were 82/94%, 49/64%, and 28/34%, respectively. In 198 SR, 154 of 160 responders and 24 of 38 nonresponders survived event-free (P<0.01). In 73 IR, 12 of 24 whose tumors remained unresectable experienced recurrence, 9 of whom were nonresponders (P<0.01). In 71 HR, chemoresponders and tumor resectability after preCTx correlated with favorable outcomes (P<0.05).

Conclusions: Evaluation of response and tumor resectability after preCTx is useful for predicting prognosis in HBLs. To improve outcomes, we should reconsider surgical procedures according to resectability and chemoresponsiveness.

Level Of Evidence: Level II.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.09.038DOI Listing
December 2016

Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells.

Cancer Sci 2016 Mar 9;107(3):233-41. Epub 2016 Feb 9.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma.
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http://dx.doi.org/10.1111/cas.12882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814252PMC
March 2016

The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.

Eur J Cancer 2016 Jan 1;52:92-101. Epub 2015 Dec 1.

Department of Surgery, University of Utah, Salt Lake City, USA.

Introduction: Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge.

Methods: Four multicenter trial groups in the world, who have performed prospective controlled studies of hepatoblastoma over the past two decades (COG; SIOPEL; GPOH; and JPLT), joined forces to form the CHIC consortium. With the support of the data management group CINECA, CHIC developed a centralized online platform where data from eight completed hepatoblastoma trials were merged to form a database of 1605 hepatoblastoma cases treated between 1988 and 2008. The resulting dataset is described and the relationships between selected patient and tumor characteristics, and risk for adverse disease outcome (event-free survival; EFS) are examined.

Results: Significantly increased risk for EFS-event was noted for advanced PRETEXT group, macrovascular venous or portal involvement, contiguous extrahepatic disease, primary tumor multifocality and tumor rupture at enrollment. Higher age (≥ 8 years), low AFP (<100 ng/ml) and metastatic disease were associated with the worst outcome.

Conclusion: We have identified novel prognostic factors for hepatoblastoma, as well as confirmed established factors, that will be used to develop a future common global risk stratification system. The mechanics of developing the globally accessible web-based portal, building and refining the database, and performing this first statistical analysis has laid the foundation for future collaborative efforts. This is an important step for refining of the risk based grouping and approach to future treatment stratification, thus we think our collaboration offers a template for others to follow in the study of rare tumors and diseases.
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http://dx.doi.org/10.1016/j.ejca.2015.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141607PMC
January 2016

Mortality and morbidity in primarily resected hepatoblastomas in Japan: Experience of the JPLT (Japanese Study Group for Pediatric Liver Tumor) trials.

J Pediatr Surg 2015 Dec 28;50(12):2098-101. Epub 2015 Aug 28.

Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima 734-8551 Japan.

Background: In the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocols (JPLT-1 and 2) for evaluating the cure rate of risk-stratified hepatoblastoma, primary resection was permitted in PRETEXT I and II cases, followed by postoperative chemotherapy.

Methods: In approximately 500 enrolled cases, resection was performed as the initial treatment in 60 cases, including all 18 PRETEXT I, 30 PRETEXT II, and 12 ruptured cases. The clinical features, surgical procedures, complications, and survival rates were compared in these three groups.

Results: All 18 PRETEXT I cases underwent complete resection by lobectomy or segmentectomy (n=14) or nonanatomical partial hepatectomy (NPH) (n=4). The 30 PRETEXT II cases underwent primary resection by right or left lobectomy (n=16), NPH (n=10), or other procedures (n=4). Of these 30 cases, operational death occurred in 1 newborn, and recurrence occurred in 7 cases (14.6%), including 6 NPH cases and 4 older cases (aged >3years). Of the 12 ruptured cases, 7 (58.3%) showed recurrence. Event-free survival rates at 5years in the 3 groups were 88%, 70%, and 32%, respectively.

Conclusions: Primary resection for PRETEXT I or II HB cases should be performed by anatomical resection according to strict surgical guidelines. More intensified chemotherapy is required for primary resected cases whose tumors have ruptured.
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http://dx.doi.org/10.1016/j.jpedsurg.2015.08.035DOI Listing
December 2015

Oncolytic viral therapy for neuroblastoma cells with Sindbis virus AR339 strain.

Pediatr Surg Int 2015 Dec 23;31(12):1151-9. Epub 2015 Aug 23.

Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan.

Purpose: With current treatment regimens, high-risk neuroblastoma (NB) remains largely incurable. Oncolytic viral therapy uses replication-competent viruses, like Sindbis virus (SINV), to kill cancers. The SINV AR339 strain is blood borne and relatively non-virulent. We evaluated the feasibility of SINV AR339 for treating human NB.

Methods: The cytotoxicity and viral growth of SINV AR339 were evaluated for five human NB cell lines, SK-N-SH, IMR-32, LAN-5, GOTO, and RT-BM-1. SINV-induced apoptosis was confirmed by TUNEL assays and PARP-1 cleavage. In vivo effects of SINV on neuroblastoma cell xenografts in nude mice were assessed by intratumoral or intravenous SINV inoculation.

Results: In five human NB cell lines, SINV infections induced remarkable cytotoxicity. The mRNA expressions of anti-apoptotic genes, Bcl-2 and Bcl-xL, in LAN-5 and RT-BM-1, which were less sensitive to SINV infection, increased in response to SINV infection, while the other NB cell lines sensitive to SINV infection failed to respond. In nude mice, intratumoral and intravenous SINV inoculations caused significant regression of NB xenograft tumors.

Conclusion: Our results suggested that SINV AR339 was significantly oncolytic against human NB. Thus, SINV showed promise as a novel therapy for treating NB.
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http://dx.doi.org/10.1007/s00383-015-3784-yDOI Listing
December 2015

Malignant rhabdoid tumor of the liver: a case report and literature review.

Pediatr Rep 2015 Feb 3;7(1):5578. Epub 2015 Mar 3.

Department of Pediatric Surgery, Graduate School of Medicine , Chiba University.

Malignant rhabdoid tumor (MRT) is a rare and aggressive malignancy associated with poor outcomes. MRT of the liver is even rarer, and little information has been described. We report the case of an 8-month-old boy with MRT of the liver. The tumor showed aggressive progression despite a multidisciplinary approach, and the patient died due to multiple organ failure 14 days after admission. Autopsy revealed the liver tumor and multiple metastases with negative immunohistochemistry for INI1/BAF47. A review of 53 cases of pediatric MRT of the liver is provided.
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http://dx.doi.org/10.4081/pr.2015.5578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387326PMC
February 2015

Radioguided localization of neuroblastomas in laparoscopic surgery using (123)I- radiolabeled metaiodobenzylguanidine.

Pediatr Blood Cancer 2015 Jul 18;62(7):1297-9. Epub 2015 Mar 18.

Department of Pediatric Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Minimally invasive surgery has become widely recognized and is commonly used for the diagnosis and treatment of neuroblastoma. However, in post-chemotherapy status or during reoperations, it is occasionally difficult to precisely locate small neuroblastoma lesions, and this becomes prominent in endoscopic surgeries, in which tactile sense is essentially lost. Herein, we report our preliminary experience in two abdominal neuroblastoma cases undergoing laparoscopic tumor resection with aid of intraoperative (123)I- metaiodobenzylguanidine (MIBG) radioguidance using a specifically designed gamma-probe. The procedure enables easier localization of viable neuroblastoma tissue, provided that the tumor shows moderate to high MIBG uptake.
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http://dx.doi.org/10.1002/pbc.25488DOI Listing
July 2015

Prognostic significance of aminopeptidase-N (CD13) in hepatoblastoma.

Pediatr Int 2015 Aug 14;57(4):558-66. Epub 2015 Jul 14.

Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Hepatoblastoma is a rare childhood malignant tumor that originates from immature hepatic cells. Aminopeptidase-N(CD13), an ectopeptidase that promotes tumor invasion and metastasis, is expressed in fetal stage hepatic progenitor cells, although its role in hepatoblastoma remains unclear.

Methods: The expression pattern of CD13 was investigated on immunohistochemistry in 30 tissue samples from 27 hepatoblastoma patients (16 with predominantly embryonal [pE] histology and 14 with predominantly fetal [pF] histology). Immunoreactive score (IRS) was used to quantify staining data, and the relationship between CD13 expression, clinicopathological factors, and clinical outcome was investigated. The biological function of CD13 was also examined in the hepatoblastoma cell lines Huh6 and HepG2.

Results: All specimens stained positive for CD13, with higher CD13 expression in pE than in pF hepatoblastoma samples (median IRS, 4; range, 2-9 vs 2; range, 1-4). Strong CD13 expression was correlated with vascular invasion. Five year event-free survival and overall survival were better in patients with CD13(low) than in those with CD13(high) tumors (100% vs 51.0%, P = 0.026; and 100% vs 74.0%, P = 0.114, respectively). A CD13-neutralizing antibody and the potent CD13 inhibitor, Ubenimex, suppressed invasive activity in HepG2 cells in vitro.

Conclusions: CD13 expression is associated with hepatoblastoma invasiveness and could be a novel prognostic marker for hepatoblastoma.
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http://dx.doi.org/10.1111/ped.12597DOI Listing
August 2015

Coexistence of neuroblastoma detected on staging of Langerhans cell histiocytosis.

Pediatr Int 2014 Aug;56(4):608-10

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.

Langerhans cell histiocytosis (LCH) is a rare proliferative disease accompanied by the accumulation of pathological Langerhans cells, which often spreads into multi-site and multi-organ systems. We here describe a girl with a history of Kawasaki disease and cervical lymphadenopathy who presented with occipital LCH. Adrenal tumor was detected on staging evaluation of LCH and was diagnosed as neuroblastoma on resection using laparoscopic surgery. Neither tumor relapsed following chemotherapy for LCH and resection of neuroblastoma. Although LCH often spreads into multi-organ lesions, invasive biopsy may be needed for tumors with atypical localization for LCH in consideration of the synchronous occurrence of malignancies.
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http://dx.doi.org/10.1111/ped.12292DOI Listing
August 2014

Histological features of primary tumors after induction or high-dose chemotherapy in high-risk neuroblastoma.

Pediatr Surg Int 2014 Sep 27;30(9):919-26. Epub 2014 Jul 27.

Department of Pediatric Surgery, Chiba Children's Hospital, 579-1 Heta-cho, Midori-ku, Chiba, 266-0007, Japan,

Purpose: In the recent years in Japan, an increasing number of patients with neuroblastoma (NB) are being treated by the "delayed local treatment (DL)" policy, undergoing surgery after the completion of high-dose chemotherapy with hematopoietic stem cell rescue (HDC). We reviewed the histopathological findings of second-look operations, including those of patients treated with DL.

Patients: From 1998 to 2013, 26 patients with high-risk NB underwent radical operation following chemotherapy. Surgery was performed after induction chemotherapy in 17 cases (standard; STD), whereas 9 cases completed induction chemotherapy and HDC before undergoing tumor resection (DL). The amount of necrosis and the degree of differentiation within the post-treatment tumor were assessed.

Results: Eighty-eight percent of the tumors showed necrosis in more than 1/3 of the specimen. Two DL cases showed complete disappearance of viable tumor cells. Amount of necrosis did not affect the prognosis of the patient. Tumors with immature, poorly differentiated phenotypes showed an extremely aggressive thereafter. Though not statistically proven, (123)I-MIBG (metaiodobenzylguanidine) uptake may be correlated with the amount of viable cells remaining within the tumor, but not with the degree of differentiation.

Conclusions: Our results support the previous reports advocating that tumors that sustain unfavorable histology after chemotherapy behave aggressively thereafter.
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http://dx.doi.org/10.1007/s00383-014-3564-0DOI Listing
September 2014