A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Correction to: 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).

In the October 2018 issue of International Journal of Clinical Oncology.

Registration-directed phase 1/2 trial of irinotecan for pediatric solid tumors.

BACKGROUND: Although irinotecan hydrochloride (IRI) is a promising chemotherapeutic agent for pediatric solid tumors, its indications had been off-label in the USA, EU and Japan. Therefore, we conducted a phase 1/2 trial of IRI monotherapy in a registration-directed setting. METHODS: Children aged 2-18 years with solid tumors who were either refractory to or relapsed after standard chemotherapy were enrolled. Phase 1 was a conventional dose escalation study to determine the dose-limiting toxicity (DLT) and the recommended dose. IRI was given i.v. on days 1, 2, 3 and 8, 9, 10 in up to eight, 21 day cycles. RESULTS: The starting dose (40 mg/m2 /day) was determined to be the recommended dose because the next higher dose level (45 mg/m2 /day) resulted in two cases of DLT. Seventeen children (11 in phase 1 and six in phase 2) with a refractory solid tumor received IRI. Of the 12 patients treated with 40 mg/m2 /day, seven (58.3%) achieved a stable disease condition for >8 weeks. CONCLUSIONS: The RD of IRI in this treatment schedule was 40 mg/m2 /day. IRI did not cause tumor shrinkage but might help to stabilize refractory pediatric solid tumors. Based on the accumulating evidence from international studies of the efficacy of IRI against refractory pediatric solid tumors, the Japanese regulatory authority approved its use for this indication in 2011.

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).

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.

Tailor-made treatment combined with proton beam therapy for children with genitourinary/pelvic rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas among children. Patients who developed genitourinary/pelvic rhabdomyosarcoma (GU/P-RMS) have a higher complication ratio and relatively poorer event free survival, with local therapy being very important. While proton beam therapy (PBT) is expected to reduce co-morbidity, especially for children, this lacks firm evidence and analysis. We analyzed GU/P-RMS children who had undergone multimodal therapy combined with PBT at a single institution. METHOD: We retrospectively reviewed charts of children with GU/P-RMS treated from January 2007 to May 2013 at the University of Tsukuba Hospital who had undergone multimodal therapy with PBT. RESULTS: There were 5 children and their median age at diagnosis was 2.8 years (0.6-4.4 years). Primary sites were the bladder (2) and the prostate (3). All received neo-adjuvant chemotherapy and 3 underwent chemotherapy during PBT (Group Cx). All patients of Group Cx developed leukocytopenia (WBC <1000/µL). The median dose of PBT was 47.7 GyE (41.4-50.4 GyE). All patients survived by their last hospital visit (median, 36 months). CONCLUSIONS: We analyzed multimodal treatment combined with PBT applied for GU/P-RMS. PBT was well tolerated and could be a plausible choice instead of photon therapy for this population.

Clinical results of proton beam therapy for advanced neuroblastoma.

PURPOSE: To evaluate the efficacy of proton beam therapy (PBT) for pediatric patients with advanced neuroblastoma. METHODS: PBT was conducted at 21 sites in 14 patients with neuroblastoma from 1984 to 2010. Most patients were difficult to treat with photon radiotherapy. Two and 6 patients were classified into stages 3 and 4, respectively, and 6 patients had recurrent disease. Seven of the 8 patients who received PBT as the initial treatment were classified as the high risk group. Twelve patients had gross residual disease before PBT and 2 had undergone intraoperative radiotherapy before PBT. Five patients received PBT for multiple sites, including remote metastases. Photon radiotherapy was used in combination with PBT for 3 patients. The PBT doses ranged from 19.8 to 45.5 GyE (median: 30.6 GyE). RESULTS: Seven patients are alive with no evidence of disease, 1 is alive with disease progression, and 6 died due to the tumor. Recurrence in the treatment field was not observed and the 3-year locoregional control rate was 82%. Severe acute radiotoxicity was not observed, but 1 patient had narrowing of the aorta and asymptomatic vertebral compression fracture at 28 years after PBT, and hair loss was prolonged in one patient. CONCLUSION: PBT may be a better alternative to photon radiotherapy for children with advanced neuroblastoma, and may be conducted safely for patients with neuroblastoma that is difficult to manage using photon beams.

Successful treatment of infants with localized neuroblastoma based on their MYCN status.

BACKGROUND: The aim of this study was to evaluate the effectiveness of post-surgical chemotherapy for infants with localized neuroblastoma without MYCN amplification (MNA), and determine whether risk classification using MNA is reasonable. METHODS: Four hundred and fourteen eligible patients were registered between 1998 and 2004. Resectable patients in stage 1 and 2A/2B were treated by surgical resection only. Unresectable patients in stage 3 without MNA received either 6 cycles of regimen A or 3 cycles of regimen A plus 3 cycles of regimen C2; regimen A consisted of low doses of cyclophosphamide and vincristine and regimen C consisted of cyclophosphamide, vincristine and pirarubicin before surgical resection. The resectable and unresectable patients were randomly selected to receive post-surgical chemotherapy. The patients with MNA received intensive chemotherapy regimen D2, consisting of cyclophosphamide, vincristine, pirarubicin and cisplatin, and some of them received high-dose chemotherapy with stem cell transplantation. RESULTS: The 5-year event-free survival (5-EFS) rates of stage 1 and 2A/2B patients without MNA were 97.2 and 89.0% respectively (p = 0.02). A total of 31 patients in stage 3 without MNA received post-surgical chemotherapy, and 30 patients did not. The 5-EFS rates of these two groups (96.0 and 96.2%, respectively) were not significantly different (p = 0.869). The 5-EFS rate for localized patients with MNA (n = 6) was 50.0%, and that of patients without MNA was 95.0% (p < 0.001). CONCLUSION: Post-surgical chemotherapy was therefore unnecessary for localized patients without MNA. This treatment strategy using MNA is considered to be appropriate in infants.

Enhanced antitumor effect of lower-dose and longer-term CPT-11 treatment in combination with low-dose celecoxib against neuroblastoma xenografts.

BACKGROUND: We have previously reported that the combination of low-dose (5.9 mg/kg/dose) irinotecan (CPT-11) and simultaneous low-dose (5 mg/kg/dose) celecoxib, a cyclooxygenase-2 inhibitor, administered for 20 consecutive days, had synergistic antitumor activity against human neuroblastoma xenografts in mice. Possible further antitumor efficacy of lower-dose and longer-term CPT-11 combined with simultaneous low-dose celecoxib was investigated for chemosensitive TNB9 and multi-drug resistant TS-N-2nu neuroblastoma xenografts. METHODS: The time from initiation of drug treatment to tumor regrowth, tumor doubling time, and body weight change of mice were evaluated between treatments with lower-dose (3 mg/kg/dose) CPT-11 alone and the combination of the two drugs for 60 consecutive days. Induction of apoptosis and autophagy during treatments were analyzed by immunoblotting, real-time quantitative RT-PCR, TUNEL assay, and immunohistochemistry. RESULTS: The combination of the two drugs administered for 60 consecutive days resulted in a significantly longer time to tumor regrowth (p < 0.011) and longer tumor doubling time (p < 0.013) in both xenografts than for the lower-dose CPT-11 therapy alone, without substantial side effects in mice. In particular, five of six TNB9 tumors treated with the combination of the two drugs showed no regrowth even 120 or 150 days after the initiation of therapy. The combined treatment suppressed the induction of autophagy leading to apoptosis in TNB9 tumors, and induced autophagy to enhance the antitumor effect in TS-N-2nu tumors. CONCLUSION: Our findings demonstrate that lower-dose and longer-term CPT-11 treatment in combination with simultaneous low-dose celecoxib enhances antitumor activity and can successfully eradicate most of the neuroblastoma xenografts.

Enteric duplication cyst of the pancreas with duplicated pancreatic duct.

Enteric duplication cyst is one of the rarest forms of cystic lesion of the pancreas. We report a unique case of an enteric duplication cyst of the pancreas that was communicating with a duplicated pancreatic duct. A 7-year-old girl with severe acute abdominal pain was found to have a large cyst that was smoothly communicating with the dilated pancreatic duct in the pancreatic tail. Analysis of cyst fluid showed elevated levels of amylase, carcinoembryonic antigen (CEA) and CA 19-9, and no epithelial cells. Intraoperative cyst pancreatography revealed that the pancreatic duct was duplicated in the tail: 1 duct was communicating with the cyst, and the other was dilated within the pancreatic tail. The patient underwent spleen-preserving distal pancreatectomy and complete cyst excision without complication. Because preoperative diagnosis of duplication cyst of the pancreas is difficult, this condition should be considered during differential diagnosis of atypical cystic lesions of the pancreas. Complete excision is desirable for the management of duplication cyst of the pancreas.

Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.

Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image-defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.

Identification of therapy-sensitive and therapy-resistant neuroblastoma subtypes in stages III, IVs and IV.

The aim was to present a new model of risk stratification with high predictive sensitivity for non-localized neuroblastomas (NBs). "MYCN amplification", "unfavorable histology of the International Neuroblastoma Pathology Classification (INPC) system" and "low Ha-ras/trk A expression" could be defined as an independent predictor for high-risk NBs. A risk stratification flow chart was applied to 103 advanced NBs in which all three factors were examined and 69 were grouped as high-risk NBs of which 38 patients died. The predictive sensitivity for poor patient outcome was 86%, which included 38 of the 44 total deaths in this analysis. Using the number of the three independent risk factors in each tumor, the 69 high-risk NBs were classified into three subgroups. NBs with the three risk factors (triple risk) represented the most aggressive character and survival of the affected patients was only 10% ("therapy-resistant NBs"). Survivals of the patients with NBs possessed the two (double) risk factors or the one (single) risk factor were 29% and 66%, respectively. This stratification also elucidated a subgroup in which patient survival was 90% ("therapy-sensitive"). There were 21 NBs with "high Ha-ras/trk A expression", "favorable INPC histology" and "unamplified MYCN" (no risk NBs). Among the four subgroups without a risk factor, with a single risk factor, with double risk and with triple risk, Kaplan-Meier analysis showed a significant difference in NB patient outcome (p<0.0001). Risk stratification might improve the therapeutic efficacy for the high-risk NBs and might decrease therapy-related sequelae in the lower risk NBs.

Pathogenic implications of remnant vitelline structures in gastroschisis.

PURPOSE: The pathogenesis of gastroschisis is unknown. It may be helpful in understanding its pathogenesis to know the structural relationships among umbilical components including umbilical vessels, urachus, and vitelline structures, and thus, the authors investigated the remnants of vitelline structures in a series of cases of gastroschisis. METHODS: Medical records of 41 cases with gastroschisis treated in our institute from 1979 to 2009 were retrospectively reviewed. RESULTS: Paraumbilical bands, possible remnants of vitelline structures, were observed in 4 cases (9.8%). All 4 bands were attached to the skin edge of the abdominal defect without incorporation into the umbilical cord. The band ended at the mesentery in 3 cases and at the antimesenteric site of the ileum in the remaining case. Histologic findings showed fibrous tissues in all cases. One was possibly associated with the development of colonic atresia. Another was noticed after silo reduction when herniated bowels became strangulated by the band. The other 2 cases were uncomplicated. CONCLUSIONS: Our findings may support the recently proposed hypothesis that the developmental failure of the yolk sac and related vitelline structures to merge with or to be incorporated into the umbilical stalk might be associated with the pathogenesis of the abdominal wall defect in gastroschisis. Paraumbilical bands derived from vitelline structures may possibly cause intestinal ischemia prenatally or postnatally.

Neural differentiation potential of rat amniotic epithelial cells.

Amniotic epithelial cells (AEC) are thought to represent a stem-like cell population and to be an attractive cell source for regenerative medicine, because abundant cells can be obtained noninvasively at delivery. The authors investigated the neural differentiation potential of rat AEC. Rat AEC expressed vimentin and nestin, but not c-kit, oct-4, or nanog. The expression of the neural lineage markers, including betaIII-tubulin, neuron specific enolase (NSE), neurofilament-M, neuroD, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), tyrosine hydroxylase (TH), acetylcholinesterase (AChE), cholin acetyltransferase (ChAT), and mammalian achaete-scute homolog1 (MASH1), was detected by RT-PCR in the cultured rat AEC. After neural induction, rat AEC dramatically changed their shapes, projecting dendrite-like structures. Immunocytochemically, approximately 20% of the induced cells expressed an immature neuronal marker, betaIII-tubulin. Our findings suggested that rat AEC might be already committed to differentiate to various neural lineages and that they could differentiate to immature neurons in vitro.

Tracheal defect repair using a PLGA-collagen hybrid scaffold reinforced by a copolymer stent with bFGF-impregnated gelatin hydrogel.

PURPOSE: We studied the regenerated cartilage in tracheal defect repair and compared the bio-materials used versus native trachea using basic fibroblast growth factor (bFGF)-impregnated gelatin hydrogel. MATERIALS AND METHODS: A full-thickness anterior defect was created in the cervical trachea of 15 experimental rabbits. The defect was implanted with a hybrid scaffold of poly(lactic-co-glycolic acid) (PLGA) knitted mesh and collagen sponge. The implanted trachea was reinforced with a copolymer stent of polycaprolactone and poly(lactic acid) coarse fiber mesh. A gelatin hydrogel was used for providing a sustained release of bFGF. The reconstructed tracheas were divided into three groups with wrapped materials; without gelatin hydrogel (control group, n = 5), a gelatin hydrogel with saline (gelatin group, n = 5), and a gelatin hydrogel with 100 microg of bFGF (bFGF group, n = 5). One of the five rabbits in each group at 1 month after operation, one at 3 months, and three at 6 months were killed and the engineered tracheas were evaluated histologically. Biomechanical properties were evaluated on samples at 6 months postoperatively. RESULTS: The rigid support in the defect portion was maintained during 6 months postoperatively. The newly regenerated cartilages were recognized between the host cartilage stumps at 3 months postoperatively in the bFGF group, and limited new cartilage growth and epithelialization were observed at 6 months postoperatively. CONCLUSIONS: The experiment shows that using bFGF, better mechanical strength was obtained but with poor cartilage growth.

Closure of the larynx for intractable aspiration in neurologically impaired patients.

We present three patients with intractable aspiration pneumonia in the setting of permanent neurologic impairment, who had received a tracheostomy and showed a juxtaposition of the innominate artery against the trachea. Neurologically impaired patients often show a juxtaposition or compression of the innominate artery against the trachea by chest deformity in the setting of severe scoliosis, which could result in a trachea-innominate artery fistula. For intractable aspiration, laryngotracheal separation is safely performed and effective in controlling aspiration, but is occasionally complicated by trachea-innominate artery fistula. As an alternative procedure, we performed a closure of the larynx in these three cases, using double flaps of the vocal folds and false vocal folds, as a treatment for intractable aspiration. After operation, the patients did well without complication or clinical evidence of recurrent aspiration.

A tissue engineering approach for prenatal closure of myelomeningocele with gelatin sponges incorporating basic fibroblast growth factor.

Myelomeningocele (MMC) is a common and devastating malformation. Although fetal surgical closure may improve outcome, a less invasive approach that can be applied earlier in gestation is desirable. The objective of this study was to evaluate the therapeutic feasibility of a tissue engineering approach for prenatal coverage of MMC. A gelatin hydrogel composite combining a gelatin sheet and gelatin sponge was prepared with or without basic fibroblast growth factor incorporation, and applied prenatally to retinoic-acid-induced fetal MMC in the rat model. Most of the composites were adherent to the MMC within the amniotic fluid environment with the help of cyanoacrylate adhesive. Histological examination revealed cells layered over the composites with associated extracellular matrix as well as cellular ingrowth into the sponges. The layer over the composite was composed of mixed nonepithelial and epithelial cells with the extracellular matrix consisting of collagen type I and hyaluronic acid. The tissue inside the sponge consisted of nonepithelial cells and hyaluronic acid. Epidermal ingrowth underneath the sponges and neovascularization into the sponges occurred and were significantly increased by the incorporation of basic fibroblast growth factor. Although further development is needed, this study supports the therapeutic potential of a tissue engineering approach for prenatal coverage of MMC.

[Late effects of cancer treatment in children--problems to be solved in adult].

As the number of childhood cancer survivors continues to increase, the problems of late effects following treatment have become a serious issue. At present, the length of follow-up for late effects of treatment largely depends on the individual treating physicians, and no follow-up teams are organized in most of Japan. Childhood cancer survivors may not only have physical handicaps but also experience psychological and social problems. The establishment of a follow-up system is a serious need in Japan and should involve physicians, other medical professionals, social workers, and cancer survivors themselves. Physicians should always consider whether the recommended treatment or surgery will yield the best results from the viewpoint of probable late effects.