Neuroblastoma is one of the most frequent, yet distinctive and challenging childhood tumors. The uniqueness of this tumor depends on its biological markers, which classify neuroblastomas into ...favorable and unfavorable, with 5-year survival rates ranging from almost 100–30%. In this review, we focus on some biological factors that play major roles in neuroblastoma: MYCN, Trk, and ALK. The MYCN and Trk family genes have been studied for decades and are known to be crucial for the tumorigenesis and progression of neuroblastoma. ALK gene mutations have been recognized recently to be responsible for familial neuroblastomas. Each factor plays an important role in normal neural development, regulating cell proliferation or differentiation by activating several signaling pathways, and interacting with each other. These factors have been studied not only as prognostic factors, but also as targets of neuroblastoma therapy, and some clinical trials are ongoing. We review the basic aspects of MYCN, Trk, and ALK in both neural development and in neuroblastoma.
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.
Background
Some neuroblastoma (NB) cases are suitable for minimally invasive surgery (MIS), but indication and technical issue are unclear. We assessed the current status of MIS for abdominal NB ...after mass screening period in Japan.
Methods
Preliminary questionnaires requesting the numbers of NB cases that underwent MIS from 2004 to 2016 were sent to 159 Japanese institutes of pediatric surgery. The secondary questionnaires were then sent to the institutions that reported MIS cases of NB in order to collect detailed data.
Results
One hundred and thirty-four (84.2%) institutions responded to the preliminary questionnaires, and 83 (52.2%) reported managing operative cases. The total number of operative cases was 1496. MIS was performed for 175 (11.6%) cases, of which the completed forms of 140 patients were returned, including 100 abdominal NB cases. The male/female ratio was 51/49. Forty-seven cases underwent a laparoscopic biopsy, and 2 (4.3%) cases were converted to laparotomy due to bleeding. Sixty-five cases underwent MIS for radical resection, and 7 (10.8%) were converted to laparotomy. The reasons for open conversion were bleeding and severe adhesion. Regarding open conversion, there were no significant relationships between conversion and neo-adjuvant chemotherapy, biopsies, stage, size, or
MYCN
amplification. We found no relationship between resectability and vascular encasement in this study. There was relationship between the resected tumor size and the patients’ height, which was expressed using the following formula:
y
=
0.0316
x
+
1.4812
(
x
, patients height,
y
, tumor size;
p
= 0.004219, SE: 1.55566). Postoperative complications after radical resection were recognized in 7 (10.8%) cases.
Conclusions
MIS was performed in limited cases of abdominal NB. A laparoscopic biopsy with careful attention to bleeding is feasible. The resected tumor size was shown to correlate with the patients’ height. Tumor size within 6 cm of maximum diameter can be resected safely.
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).
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.
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.
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.
We reported the in vitro and in vivo anti-tumor effects of trametinib, an MEK inhibitor, on neuroblastoma. However, long-term trametinib administration for bulky tumors failed to prevent local ...relapse. In this study, we established a local minimal residual disease (L-MRD) model to develop an optimal clinical protocol.
We prepared an l-MRD model by implanting neuroblastoma cells (SK-N-AS) into the renal capsule of nude mice with total tumorectomy or sham operation 14 days later. These mice received post-operative administration of trametinib or vehicle for eight weeks. Relapse was measured once weekly. Flow cytometry was performed with SK-N-AS cells treated by trametinib.
Tumorectomy+trametinib dramatically suppressed relapse, and all mice survived during trametinib administration, while other treatments failed to suppress relapse. The survival rates for other groups were 20% in sham+trametinib, 17% in tumorectomy+vehicle, and 0% in sham+vehicle. Relapse occurred in the tumorectomy+trametinib group after withdrawal of trametinib administration. Flow cytometry revealed G1 arrest in SK-N-AS cells treated with trametinib.
These findings suggested that trametinib was able to suppress relapse from minimal residual tumor cells. Therefore, we propose that trametinib be administered as an option for maintenance therapy after surgical and chemotherapeutic treatments for neuroblastoma in future clinical protocols.
Purpose
The majority of relapsed neuroblastomas have mitogen-activated protein kinase (MAPK) pathway activating mutations. We previously showed the in vitro and in vivo anti-tumor effects of MAPK/ERK ...kinase (MEK) inhibitors in MAPK-activated neuroblastoma. We herein assessed the correlation between MAPK activation and the prognosis in neuroblastoma patients using phosphorylated extra-cellular signal-regulated kinase (pERK) immunohistochemistry to establish the protocol for the clinical administration of MEK inhibitors.
Methods
Neuroblastoma samples from patients treated in our hospital were immunostained with pERK. The clinical outcomes were retrospectively collected from medical records. The correlation between pERK positivity and the prognosis was analyzed.
Results
Regarding pre-chemotherapeutic specimens, there were no differences in the pERK status between tumors with a good and bad prognosis in both the nuclei and cytoplasm. Regarding post-chemotherapeutic specimens, one of eight tumors with a good prognosis and four of six tumors with a poor prognosis showed pERK-positive nuclear staining (
p
= 0.0909) and five of eight tumors with a good prognosis and four of six tumors with a poor prognosis showed pERK-positive cytoplasmic staining (
p
> 0.9999).
Conclusion
These findings suggested post-chemotherapeutic—not pre-chemotherapeutic—nuclear pERK-positive neuroblastoma tends to be associated with a poor prognosis and may be a potential therapeutic target for MEK inhibitor treatment.
Precision medicine strategies for treating rhabdomyosarcoma (RMS), a childhood malignancy, have not been developed. We examined the effect of CH5126766, a potent selective dual RAF/MEK inhibitor, on ...RMS cell lines. Among the eleven cell lines studied, one NRAS and two HRAS mutated cell lines were detected. CH5126766 inhibited the proliferation and growth in all of the RAS-mutated RMS cell lines, while it induced G1 cell cycle arrest in two of them. G1 cell cycle arrest was accompanied by p21 up-regulation and RB dephosphorylation. CH5126766 also suppressed the in vivo growth of RAS-mutated RMS tumor, and the mice showed improved survival. Thus, our results demonstrate that CH5126766 is an effective RAF/MEK inhibitor in RAS-mutated RMS. This study not only shows that in RMS, mutations in the RAS pathway can be a target for precision medicine, but also demonstrates that the evaluation of the gene mutation status is important in childhood malignancies.
•Precision medicine is lacking the treatment of childhood rhabdomyosarcoma (RMS).•Embryonic RMS shows genotypic variability with respect to RAS pathway mutations.•CH5126766, a novel RAF/MEK inhibitor, is effective against RAS-mutated RMS.•RAS mutations may serve as targets in precision medicine for RMS.
We herein report a rare case of mesenchymal hamartoma of the chest wall in a 10-year-old girl. She complained of chest pain and was diagnosed with a large chest wall tumor originating from the left ...fourth rib. Malignancy such as osteosarcoma or chondrosarcoma could not be ruled out with imaging studies. Therefore, we performed a core needle biopsy assisted by thoracoscopy, which revealed no malignancy. Therefore, extended resection with chest wall reconstruction was unnecessary, and thoracoscopy-assisted tumor excision with only the removal of the involved fourth rib was performed without chest wall reconstruction. The postoperative course was satisfactory with no thoracic deformity and no recurrence.
Objectives
Pyriform sinus cyst (PSC) and pyriform sinus fistula (PSF) is a rare congenital malformation that arises from the third or fourth branchial structure. In our study, we describe the safety ...and the utility of endoscopic electrocauterization against PSC/PSF.
Methods
We retrospectively reviewed the records of patients who underwent endoscopic electrocauterization for PSC/PSF at our hospital. The internal opening of the fistula was identified under general anesthesia using a flexible endoscope (XQ‐260 or H‐290; Olympus, Tokyo, Japan), and the DualKnifeJ (KD‐655L; Olympus) was used to ablate the internal opening.
Results
We experienced three PSF and three PSC patients. The postoperative course was uneventful in all cases. The patients declared no pain in the neck, and there were no cases showing recurrent nerve paralysis. Five in six cases (83%), the closure of fistula was archived in the first cauterization. One case (16.6%) required repeated cauterization. No recurrence was found during the follow‐up period ( median: 1 year) in any cases.
Conclusions
Owing to its rarity in neonates, the diagnosis and treatment of PSC remains complicated and not clearly described. Complete removal of the fistula and the cyst with or without affected thyroid tissue was previously the most commonly used treatment. From our experience, we believe that endoscopic electrocauterization can be the first choice not only for PSF but also for neonatal PSC. In conclusion, endoscopic electrocauterization is feasible even for neonatal PSC. Further investigations including multicenter analyses are needed.
There is no standard timing for switching to surgical management for children with adhesive small bowel obstruction (ASBO) who initially receive conservative treatment. We hypothesized that an ...increased gastrointestinal drainage volume may indicate the need for surgical intervention.
The study population included 150 episodes in the patients less than 20 years of age who received treatment for ASBO in our department from January 2008 to August 2019. Patients were divided into two groups: the successful conservative treatment group (CT) and the eventual surgical treatment group (ST). Following the analysis of all episodes (Study 1), we limited our analysis to only first ASBO episodes (Study 2). We retrospectively reviewed their medical records.
There were statistically significant differences in the volume on the 2nd day in both Study 1 (9.1 ml/kg vs. 18.7 ml/kg; p < 0.01) and study 2 (8.1 ml/kg vs. 19.7 ml/kg; p < 0.01). The cut-off value was the same for both Study 1 and Study 2 (11.7 ml/kg).
The gastrointestinal drainage volume on the 2nd day in ST was significantly larger than that in CT. Accordingly, we considered that the drainage volume may predict eventual surgical intervention for children with ASBO who initially receive conservative treatment.
Level IV.
•A significantly larger total volume of intestinal decompression on the 2nd hospital day may be an indicator for surgery.
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