Stage IV-S Research Articles

PROGNOSTIC VALUE OF N-MYC GENE AMPLIFICATION IN PATIENTS WITH NEUROBLASTOMA

This work presents the results of studying the prognostic value of the N-MYC gene amplification in patients with neuroblastoma treated according to the European protocol NB-2004. A retrospective analysis of 140 patients who were diagnosed with neuroblastoma from 2013-2019 was carried out at the SCP and PS. When collecting data from 140 patients with neuroblastoma, amplification of the N-MYC gene was found in 26 patients, of which 19 patients died (73%), 7 patients are alive (survival rate -27%). Amplification of the NMYC gene occurred with the same frequency in boys and girls, 50% in each group. In children under one year old, there were 6 children (23.1%), 1-2 years old 12 patients (46.2%), 2-5 years old 5 children (19.2%), over 5 years old 3 patients (11.5%). In 13 (50%) children, the primary tumor was localized in the adrenal glands, in 11 (42%) - in the retroperitoneal space and in 2 (7.7%) in the mediastinum. In 21 (80.8%) patients with amplification of the N-MYC gene, the disease was diagnosed at stage IV, in 2 cases (7.7%) with stage IVs, and 1 (3.8%) case at I, II, III stage of the disease. Thus, patients with N-MYC gene amplification were more often detected at stage IV of the disease and had an unfavorable outcome.The fact of the negative impact of amplification of the N-MYC gene is confirmed in our study. The therapeutic protocol is ineffective in the presence of N-MYC gene amplification (survival - 27%). Keywords: Neuroblastoma, NMYC gene amplification, prognosis, children.

PROGNOSTIC VALUE OF N-MYC GENE AMPLIFICATION IN PATIENTS WITH NEUROBLASTOMA

This work presents the results of studying the prognostic value of the N-MYC gene amplification in patients with neuroblastoma treated according to the European protocol NB-2004. A retrospective analysis of 140 patients who were diagnosed with neuroblastoma from 2013-2019 was carried out at the SCP and PS. When collecting data from 140 patients with neuroblastoma, amplification of the N-MYC gene was found in 26 patients, of which 19 patients died (73%), 7 patients are alive (survival rate -27%). Amplification of the NMYC gene occurred with the same frequency in boys and girls, 50% in each group. In children under one year old, there were 6 children (23.1%), 1-2 years old 12 patients (46.2%), 2-5 years old 5 children (19.2%), over 5 years old 3 patients (11.5%). In 13 (50%) children, the primary tumor was localized in the adrenal glands, in 11 (42%) - in the retroperitoneal space and in 2 (7.7%) in the mediastinum. In 21 (80.8%) patients with amplification of the N-MYC gene, the disease was diagnosed at stage IV, in 2 cases (7.7%) with stage IVs, and 1 (3.8%) case at I, II, III stage of the disease. Thus, patients with N-MYC gene amplification were more often detected at stage IV of the disease and had an unfavorable outcome.The fact of the negative impact of amplification of the N-MYC gene is confirmed in our study. The therapeutic protocol is ineffective in the presence of N-MYC gene amplification (survival - 27%). Keywords: Neuroblastoma, NMYC gene amplification, prognosis, children.

Bottom up proteomics identifies neuronal differentiation pathway networks activated by cathepsin inhibition treatment in neuroblastoma cells that are enhanced by concurrent 13-cis retinoic acid treatment

Neuroblastoma is the second most common pediatric cancer involving the peripheral nervous system in which stage IVS metastatic tumors regress due to spontaneous differentiation. 13-cis retinoic acid (13-cis RA) is currently used in the clinic for its differentiation effects and although it improves outcomes, relapse is seen in half of high-risk patients. Combinatorial therapies have been shown to be more effective in oncotherapy and since cathepsin inhibition reduces tumor growth, we explored the potential of coupling 13-cis RA with a cathepsin inhibitor (K777) to enhance therapeutic efficacy against neuroblastoma. Shotgun proteomics was used to identify proteins affected by K777 and dual (13-cis RA/K777) treatment in neuroblastoma SK-N-SH cells. Cathepsin inhibition was more effective in increasing proteins involved in neuronal differentiation and neurite outgrowth than 13-cis RA alone, but the combination of both treatments enhanced the neuronal differentiation effect. SignificanceAs neuroblastoma can spontaneously differentiate, determining which proteins are involved in differentiation can guide development of more accurate diagnostic markers and more effective treatments. In this study, we established a differentiation proteomic map of SK-N-SH cells treated with a cathepsin inhibitor (K777) and K777/13-cis RA (dual). Bioinformatic analysis revealed these treatments enhanced neuronal differentiation and axonogenesis pathways. The most affected proteins in these pathways may become valuable biomarkers of efficacy of drugs designed to enhance differentiation of neuroblastoma [1].

A five-year review of children with neuroblastoma at Dr. Sardjito General Hospital, Yogyakarta, Indonesia

Background Neuroblastoma is the third most common tumor in children, after leukemia and retinoblastoma. The disease presents with a wide range of symptoms.
 Objective To assess the clinical profiles of children with neuroblastoma at Dr. Sardjito General Hospital from 2012-2016.
 Methods A retrospective review of all children with neuroblastoma under 18 years of age in the Children’s Ward of Dr. Sardjito General Hospital, Yogyakarta from 2012-2016. Patients diagnosed and treated in other hospitals were excluded. Data were taken from the Yogyakarta Pediatric Cancer Registry (YPCR) and medical records. Outcomes were assessed by patient status: alive, died, or lost to follow-up.
 Results A total of 40 subjects were included in this study. Six (15.0%) patients were diagnosed at <1 year of age, 26 (65.0%) patients at 1 to <5 years of age, 6 (15.0%) patients at 5 to <10 years of age, and 2 (5.0%) patients at ≥10 years of age. The male to female ratio was 1.5:1. Four (10.0%) patients had stage IV-S, 34 (85.0 %) patients had stage IV, and 2 (5.0 %) patients had stage II/III of the disease. Proptosis (40.0%) and abdominal mass (35.0%) were the most common chief complaints. Eight (20.0%) patients were alive at the end of observation, 15 (37.5%) died, and 17 (42.5%) were lost to follow-up. The deaths were mostly caused by sepsis.
 Conclusion Most patients are diagnosed at the age of 1 to <5 years, with a median age of 3 years. Proptosis is the most common chief complaint. Most patients present in stage IV. Overall survival rate is very low. The high numbers of lost to follow-up should be noted.

Clinical analysis of neuroblastoma in 36 children

Objective To explore the diagnosis, treatment and prognosis of neuroblastoma in children. Methods The clinical data of 36 children with neuroblastoma admitted to Department of Pediatric Surgery, Henan Provincial People′s Hospital between August 2013 and August 2018, were retrospectively analyzed. The patients included 22 males and 14 females with the age of 1 month-13 years old [( 20.0±18.5) months]. Twenty-one cases of neuroblastoma originated from the adrenal glands, the other 15 cases from the sympathetic ganglion(including 7 cases in retroperitoneum, 6 cases in postmediastinum, and 2 cases in neck). Fifteen patients in low risk and intermediate risk groups underwent primary surgery before multiple chemotherapy, while other 21 cases in high risk groups underwent chemotherapy until the mass could be removed completely, then continuely underwent multiple chemotherapy. Results Of the 36 patients, 23 cases(63.9%) had a radical resection, 13 patients underwent palliative resection and 2 patients were treated with vascular repair during surgery (abdominal aorta in 1 patient, inferior vena cava in 1 patient). Twenty-seven patients had effective in formation and 16 patients survived, during follow-up, 12 patients belonged to stage Ⅰ-Ⅲ disease, 2 patients stage Ⅳ disease and 2 patients stage Ⅳs disease, respectively.Four cases underwent re-operation due to disease recurrence, then they underwent chemothearopy, and 3 patients were survival with tumor. Conclusions Neuroblastoma is a highly malignant pediatric cancer accompanied with a high rate of metastasis on initial diagnosis.Radical resection is an effective therapeutic strategy for improving the survival rate. If radical resection is impractical, palliative resection combined with chemotherapy can significantly prolong patients′ survival time.And a better prognosis is achieved if it can be early diagnosed and treated timely. Key words: Neuroblastoma; Diagnosis; Surgical operation; Retrospective study

Clinical Characteristics of Peripheral Neuroblastic Tumors in Children: A Single-Center Experience of 43 Cases

Background: The true incidence of peripheral neuroblastic tumors (PNTs) in children is unknown. This study aims to review and analyze clinical data on the diagnosis and management of pediatric PNTs. Methods: Between 2007 and 2016, a total of 43 pediatric patients admitted to our institute with PNTs were reviewed. Results: The series comprised of 23 males and 20 females with a median age of 1.2 years old. Among the 43 PNTs, 26 tumors originated from the abdomen, 13 from the thorax and four from other primary sites. A total of 16 tumors were identified in routine examinations. Abdominal pain and distension were the main clinical manifestations of abdominal PNTs, while coughing was the most frequent presenting symptom of thoracic PNTs. Elevated vanillylmandelic acid level in the urine over 24 hours was observed in 18 neuroblastoma cases and three ganglioneuroblastoma cases. Neuroblastoma was the most common type of PNT that was reported in 30 (69.8%) patients, followed by ganglioneuroblastoma, which was diagnosed in 11 (25.6%) patients. Only 2 (4.6%) patients were diagnosed with ganglioneuroma. A total of 12 cases were stage, six cases were stage II, three cases were stage III, 18 cases were stage IV, and four cases were stage IVs. The overall two year survival rate was 62.9%, which was related to pathological type, Shimada classification, stage, and primary site. Conclusions: Pediatric PNTs have different clinical characteristics and outcomes. Imaging and laboratory data may be useful for the differentiation of PNTs. This study will help pediatric surgeons be aware of the possible manifestations of PNTs in children.

Long-term prognosis of low-risk neuroblastoma treated by surgery alone: an experience from a single institution of China.

Low-risk neuroblastomas have favorable biologic characteristics. Children Oncology Group (COG) proposed that surgical resection of the primary tumor was sufficient. We evaluated the long-term prognosis of surgery alone for patients with low-risk neuroblastoma in China. A total of 34 patients with low-risk neuroblastoma were treated in our center between Jan 2009 and Dec 2013. The medical records of these patients were reviewed. The primary lesion was located in the adrenal gland in 19 patients, the retroperitoneum in 5, the posterior mediastinum in 9 and the neck in 1. The tumor diameters and volumes were 1.80-10.0cm (average 5.5 ± 2.3cm) and 1.28-424.10cm3 (average 58.81 ± 92.00cm3), respectively. The stages of the patients were as follows: stage I in 25, stage II in 7, and stage IVs in 2. All patients were in the low-risk group according to COG risk stratification criteria. No patients showed MYCN amplification. The primary tumors of all patients were completely resected. Nine adrenal tumors were completely resected by laparoscopy. All patients were successfully followed for 66-115 (average 89.71 ± 16.17) months. Recurrence was observed in 4 patients. In addition to one local recurrence, another three recurrences were metastases. The lesions were effectively controlled in all patients with recurrences. All patients survived, including 28 cases of tumor-free survival; the 4-year overall and event-free survival rates were both 100%. Surgery alone is a safe and effective treatment strategy for low-risk neuroblastoma. Recurrent lesions may be controlled and treated by rescue chemotherapy and surgery.

Expression and significance of programmed cell death ligand-1 in neuroblastoma tissues

Objective: To investigate the relationship between expression of programmed cell death ligand-1(PD-L1) in the tissue of neuroblastoma (NB) and patient's clinical characteristics and prognosis. Methods: Clinical data and surgical tissue paraffin blocks of 100 newly diagnosed NB children at Sun Yat-sen University Cancer Center between January 2000 and December 2015 were collected and the expression level of PD-L1 and its' relationship with pathological parameters and survival rate were analyzed retrospectively. The ratio between groups was compared by chi-square test. Kaplan-Meier method was used for survival analysis and COX regression model was used for multivariate analysis. Results: Among 100 cases, 71 were males and 29 females; there were 5 cases of stageⅠ, 4 cases of stageⅡ, 19 cases of stage Ⅲ, 65 cases of stage Ⅳ and 7 cases of stage Ⅳs. Ten out of 62 cases (16%) were N-MYC amplified; 15 cases were in low-risk group, 18 were in medium-risk group and 67 were in high-risk group. The positive rate of PD-L1 in NB tumor tissue was 57% (57/100), of which 55 were weakly positive, 1 was moderately positive and 1 was strongly positive. The positive rates of PD-L1 expression in tumor tissues without bone metastasis were higher than those with bone metastasis(66%(39/59)vs.44%(18/41), χ(2)=4.864, P=0.027), the positive rates of PD-L1 expression in tumor tissues pathologically diagnosed as neuroblastoma were higher than those pathologically diagnosed as ganglioneuroblastoma (61%(53/87) vs.31%(4/13), χ(2)=4.195, P=0.041), the positive rates of PD-L1 expression in tumor tissues originated from abdominal cavity were higher than those originated from other places (61% (51/83)vs.35%(6/17), χ(2)=3.937,P=0.047).The 4-year event-free survival (EFS) rates of patients with PD-L1 negative and positive were 40% and 33% (χ(2)=0.009, P=0.923), respectively. The 4-year overall survival (OS) rates of patients with PD-L1 negative and positive were 62% and 58% (χ(2)=0.294, P=0.587). Among 33 non-high-risk patients, the 4-year EFS rates of patients with PD-L1 negative and positive were 89% and 78% (χ(2)=0.001, P=0.965), the 4-year OS rates of patients with PD-L1 negative and positive were 100% and 96% (χ(2)=0.500, P=0.480). Among 67 high-risk patients, the 4-year EFS rates of patients with PD-L1 negative and positive were 24% and 11% (χ(2)=1.154, P=0.282), the 4-year OS rates of patients with PD-L1 negative and positive were 48% and 41% (χ(2)=0.692, P=0.405). Multivariate analysis showed that N-MYC gene amplification was an independent adverse prognostic factor for OS and EFS rates of NB patients (RR: 1.726,95%CI:1.209-2.466; RR:1.326,95%CI:1.014-1.736) and advanced clinical stage was an independent adverse prognostic factor for EFS rates of NB patients (RR: 26.498, 95%CI:3.518-199.614). Conclusions: The expression of PD-L1 in NB tumor tissues was correlated with the clinical characteristics of children. However, there were no significant differences in the prognosis of patients with or without PD-L1 expression.

Impact of Treatment Intensification According to Patient Prognosis: A Pooled Analysis of 3 Randomized Phase III Trials

Introduction : Risk-adapted therapy in curable hematologic malignancies is commonly applied: low-risk patients (pts) may be cured with less intensive treatment, avoiding excessive toxicity, whereas high-riskpts require more intensive and toxic regimens. In multiple myeloma (MM), this model may not apply, since the disease is incurable. In recent years, there has been a marked improvement in patient outcome, due to the introduction of novel agents and optimized treatment strategies, including the use of transplant and maintenance. A better evaluation ofpts prognosis based on the new revised international staging system (R-ISS) has been also introduced in clinical practice. The objective of this analysis was to evaluate the impact of treatment intensification (specifically autologous stem cell transplantation [ASCT] and maintenance) inpts with different prognostic features. Methods : Data from 3 phase III randomized trials in newly diagnosed MMpts (RV-MM-209; EMN441; GIMEMA-MM0305) were pooled together and analyzed. Baseline patient risk assessment was estimated using R-ISS. We evaluated: 1) the impact of treatment intensification with high-dose therapy followed by ASCTvs no-ASCT inpts with R-ISS Stage Ivs Stage II/III; 2) the impact of treatment intensification with maintenancevs no maintenance inpts with R-ISS Stage Ivs Stage II/III. RV-MM-209 and EMN441 studies randomizedpts to ASCTvs no-ASCT; allpts in the GIMEMA-MM0305 trial did not receive ASCT and were excluded from the first comparison; RV-MM-209 and GIMEMA-MM0305 studies randomizedpts to maintenance or no maintenance after induction/consolidation; allpts in the EMN441 trial received maintenance and were excluded from the second comparison. We evaluated progression free survival-1 (PFS1), PFS2 and overall survival (OS). Cox proportional hazards models were used to estimate hazard ratios (HRs). To account for potential confounders, the comparisons between ASCTvs no-ASCT and maintenancevs no maintenance were adjusted for the trial effect and the main prognostic features. Results: Overall, 1302 pts were enrolled in the 3 trials. Median follow-up was 4 years.Comparison ASCTvs no-ASCT: 791pts were enrolled in the 2 trials, 529 were eligible for the ASCTvs no ASCT comparison. R-ISS Stage data were available for 419 pts. There was an overall advantage for ASCTvs no-ASCT in PFS1 (0.53; p Conclusions: Both ASCT and maintenance improved PFS1, PFS2 and OS in MM pts. The highest survival was reported in patients with R-ISS Stage I receiving ASCT and/or maintenance. Low-riskpts (R-ISS Stage I) not undergoing intensification with ASCT or maintenance lose their prognostic advantage over high-risk patients receiving the same intensification. Disclosures Gay: Janssen-Cilag: Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board. Hajek: Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Bringhen: Mundipharma: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: Advisory Board; Celgene: Honoraria. Gaidano: Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Caravita: Janssen-Cilag: Honoraria. Cavo: Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foa: Pfizer: Speakers Bureau; Ariad: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Patriarca: Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; Janssen-Cilag: Other: Advisory board; MSD: Consultancy; Celgene: Consultancy. Ria: Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau. Palumbo: Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Impact of Treatment Intensification According to Patient Prognosis: A Pooled Analysis of 3 Randomized Phase III Trials

Introduction: Risk-adapted therapy in curable hematologic malignancies is commonly applied: low-risk patients (pts) may be cured with less intensive treatment, avoiding excessive toxicity, whereas high-riskpts require more intensive and toxic regimens. In multiple myeloma (MM), this model may not apply, since the disease is incurable. In recent years, there has been a marked improvement in patient outcome, due to the introduction of novel agents and optimized treatment strategies, including the use of transplant and maintenance. A better evaluation ofpts prognosis based on the new revised international staging system (R-ISS) has been also introduced in clinical practice. The objective of this analysis was to evaluate the impact of treatment intensification (specifically autologous stem cell transplantation [ASCT] and maintenance) inpts with different prognostic features.Methods: Data from 3 phase III randomized trials in newly diagnosed MMpts (RV-MM-209; EMN441; GIMEMA-MM0305) were pooled together and analyzed. Baseline patient risk assessment was estimated using R-ISS. We evaluated: 1) the impact of treatment intensification with high-dose therapy followed by ASCTvs no-ASCT inpts with R-ISS Stage Ivs Stage II/III; 2) the impact of treatment intensification with maintenancevs no maintenance inpts with R-ISS Stage Ivs Stage II/III. RV-MM-209 and EMN441 studies randomizedpts to ASCTvs no-ASCT; allpts in the GIMEMA-MM0305 trial did not receive ASCT and were excluded from the first comparison; RV-MM-209 and GIMEMA-MM0305 studies randomizedpts to maintenance or no maintenance after induction/consolidation; allpts in the EMN441 trial received maintenance and were excluded from the second comparison. We evaluated progression free survival-1 (PFS1), PFS2 and overall survival (OS). Cox proportional hazards models were used to estimate hazard ratios (HRs). To account for potential confounders, the comparisons between ASCTvs no-ASCT and maintenancevs no maintenance were adjusted for the trial effect and the main prognostic features.Results: Overall, 1302 pts were enrolled in the 3 trials. Median follow-up was 4 years.Comparison ASCTvs no-ASCT: 791pts were enrolled in the 2 trials, 529 were eligible for the ASCTvs no ASCT comparison. R-ISS Stage data were available for 419 pts. There was an overall advantage for ASCTvs no-ASCT in PFS1 (0.53; p<0.001), PFS2 (HR 0.53; p<0.001) and OS (HR 0.51; p<0.001). The 4-year PFS1 was 53% inpts with R-ISS Stage I randomized to ASCT, 35% inpts with R-ISS Stage II/III randomized to ASCT, 36% inpts with R-ISS Stage I randomized to no-ASCT and 19% in those with R-ISS Stage II/III randomized to no-ASCT (p<0.001); the 4-year PFS2 was 83%, 60%, 71% and 43% in the 4 subgroups, respectively (p<0.001) (Figure 1A, B); the4-year OS was 95%, 75%, 88% and 61%(p<0.001). Comparison maintenancevs no maintenance: 913pts were enrolled in the 2 trials, 550 could be eligible for maintenance. R-ISS data were available in 403 pts. Maintenance significantly improved PFS (HR 0.54, p<0.001), PFS2 (HR 0.52, p<0.001) and OS (HR 0.69, p=0.027) in comparison with no maintenance. The 4-year PFS was 48% forpts with R-ISS Stage-I assigned to maintenance, 37% forpts with R-ISS Stage II/III assigned to maintenance, 25% forpts with R-ISS Stage-I assigned to no maintenance and 18% forpts with R-ISS Stage II/III assigned to no maintenance (p<0.001); the 4-year PFS2 was 73%, 66%, 59% and 43% in the 4 subgroups, respectively (p<0.001) (Figure 1C, D); the 4-year OS was 80%, 73%, 77% and 63% (p<0.001).Conclusions: Both ASCT and maintenance improved PFS1, PFS2 and OS in MM pts. The highest survival was reported in patients with R-ISS Stage I receiving ASCT and/or maintenance. Low-riskpts (R-ISS Stage I) not undergoing intensification with ASCT or maintenance lose their prognostic advantage over high-risk patients receiving the same intensification. [Display omitted] DisclosuresGay:Janssen-Cilag: Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board. Hajek:Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Bringhen:Mundipharma: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: Advisory Board; Celgene: Honoraria. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Caravita:Janssen-Cilag: Honoraria. Cavo:Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foà:Pfizer: Speakers Bureau; Ariad: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Patriarca:Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; Janssen-Cilag: Other: Advisory board; MSD: Consultancy; Celgene: Consultancy. Ria:Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse.

Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor kinase that belongs to the insulin receptor superfamily and has previously been shown to play a role in cell proliferation, migration and invasion in neuroblastoma. Activating ALK mutations are reported in both hereditary and sporadic neuroblastoma tumours, and several ALK inhibitors are currently under clinical evaluation as novel treatments for neuroblastoma. Overall, mutations at codons F1174, R1275 and F1245 together account for ∼85% of reported ALK mutations in neuroblastoma. NBLW and NBLW-R are paired cell lines originally derived from an infant with metastatic MYCN amplified Stage IVS (Evans Criteria) neuroblastoma, at diagnosis and relapse, respectively. Using both Sanger and targeted deep sequencing, this study describes the identification of distinct ALK mutations in these paired cell lines, including the rare R1275L mutation, which has not previously been reported in a neuroblastoma cell line. Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALK inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALK inhibitor induced apoptosis compared with NBLW cells. This pair of cell lines represents a valuable pre-clinical model of clonal evolution of ALK mutations associated with neuroblastoma progression.

Linking rising pCO2 and temperature to the larval development and physiology of the American lobster (Homarus americanus)

Few studies have evaluated the joint effects of elevated temperature and pCO2 on marine organisms. In this study we investigated the interactive effects of Intergovernmental Panel on Climate Change predicted temperature and pCO2 for the end of the 21st century on key aspects of larval development of the American lobster, Homarus americanus, an otherwise well-studied, iconic, and commercially prominent species in the northeastern United States and Atlantic Canada. Our experiments showed that larvae (stages I–III) and postlarvae (stage IV) reared in the high temperature treatments (19 °C) experienced significantly lower survival, developed twice as fast, and had significantly higher oxygen consumption rates, than those in ambient treatments (16 °C). Larvae from the ambient temperature/high pCO2 (750 ppm) treatment had significantly longer carapace lengths, greater dry masses in stages I–III and higher C: N ratios in stage IV than larvae from all other treatments. Stage IVs raised in the high pCO2 treatment at 19 °C had significantly higher feeding rates and swimming speeds than stage IVs from the other three treatments. Together these results suggest that projected end-century warming will have greater adverse effects than increased pCO2 on larval survival, and changing pCO2 may have a complex effect on larval metabolism and behaviour. Understanding how the most vulnerable life stages of the lobster life cycle respond to climate change is essential in connecting the northward geographic shifts projected by habitat quality models, and the underlying physiological and genetic mechanisms that drive their ecology.

Abdominal Compartment Syndrome Due to Liver Metastases of Stage IV-S Neuroblastoma - is Liver Transplantation a Reasonable Option?

Background: Stage IV-S neuroblastoma in infancy has a good prognosis with a high rate of complete remission. Some patients develop extended hepatic metastases with the risk of an abdominal compartment syndrome and subsequent liver failure. Liver transplantation as a life saving procedere has not been established yet. Case report: An abdominal mass led to the diagnosis of a neuroblastoma of the right glandula adrenalis in a six week-old boy. With the evidence of liver metastases and bone marrow infiltration less than 1% the diagnosis of a stage IV-S neuroblastoma was made. Because of the expected good prognosis a chemotherapy was not started immediately. In the following time the child devoloped extensive liver metastases with consequent abdominal compartment syndrome. A chemotherapy was started and at the same time several abdominal extensions with abdominal patches were performed. Nevertheless, the tumor size did not decrease and the patient developed an acute liver failure due to impaired liver perfusion. Because of acute deterioration of liver function with coagulopathy and hyperammonemia the patient was listed for emergency liver transplantation. A further course of chemotherapy was declined because the histology of the liver did only show few vital tumor cells but in contrast extended liver necrosis. The child received a liver transplant (left lateral split of a deceased donor, graft weight 550 g; graft-to-recipient weight-ratio: 11%) at the age of 3 months (body weight: 5 kg); the adrenal neuroblastoma was removed simultaneously. Because of the large-for-size situation there was a continuous impaired transplant perfusion leading to re-transplantation (left lateral split of a child, graft weight: 250 g; graft-to-recipient weight-ratio: 5%). The postoperative course was complicated by a very delayed abdominal closure and recurrent infections. The patient has a good liver function 3 months after liver transplantation without tumor recurrence and without necessity of further chemotherapy. Conclusion: Liver transplantation can be a life-saving option for infants with stage IV-S neuroblastoma and liver failure due to abdominal compartment syndrome. Because of the general good prognosis of this tumor, the need of a post-operative chemotherapy has to be discussed when the primary neuroblastoma is removed simultaneously during transplantation procedere. Problems can occur as a result of skin retraction during prolonged abdominal closure.

Cytogenetic aberrations in gliomas and their importance for diagnosis and treatment prediction

The most common brain tumors in children are neuroblastomas, whereas gliomas predominate in adults. Both tumours are known for their aggressive proliferation and diffuse invasive potential. The survival rate for patients with gliomas is less than 50%. However, the prognosis of individual cases with these brain tumours is highly variable and associated with a vast number of biological and clinical features. For example, the mortality in children with stage II and IV, younger than 12 months and with amplification of N-MYC gene exceeds 60%, while almost 100% of children in stage IVS, older than 12 months survive even without treatment.

Radiation-Associated Kidney Injury

The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy-associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients.

Clinical features and surgical outcome of a suprarenal mass detected before birth

With the widespread use of the obstetrical ultrasound, identification of a fetal suprarenal mass has become more common. Most of these masses prove to be congenital neuroblastomas (CNB), but the diagnosis is often confused with other benign lesions and the postnatal management remains to be controversial. The medical records of 18 patients that underwent primary surgical excision for an antenatally detected suprarenal mass, between January 1995 and April 2009, were reviewed. The clinical, radiological, surgical, and pathological data were collected. Staging evaluation was performed after histological confirmation of the CNB. There were 13 cases of CNB, 1 adrenal cyst, 2 adrenal hemorrhages, and 2 pulmonary sequestrations. The differential diagnosis was impossible before surgery. Most of the CNBs were stage I (N = 11), with 1 stage IV and 1 stage IV-S. Four patients (3 stage I and 1 stage IV-S) had more than one copy of N-myc gene. The stage I patients were cured by surgery alone, and stage IV patients underwent nine cycles of adjuvant chemotherapy and currently have no evidence of disease. The five benign lesions were cured with excision alone. There were no postoperative complications. For early diagnosis and treatment, surgical excision should be considered as the primary therapy for an antenatally detected suprarenal mass. The surgery can be safely performed during the neonatal period and provides a cure in most cases.

Peripheral blood stem cell recovery following early termination of apheresis due to hypotension in a 4.8‐kg infant

We report a case in which peripheral blood stem cells (PBSC) were successfully recovered following early termination of a collection procedure due to hypotension in a 7-month-old patient. The patient was diagnosed at 4 months of age with neuroblastoma stage IV-S with favorable Shimada histology. She had completed two cycles of chemotherapy before the PBSC collection (PSCC). The procedure was performed on the Cobe Spectra in manual mode, and terminated after 35 min due to severe hypotension. Etiologies considered for the hypotensive episode included a transfusion reaction to the unit of red blood cells (RBC) used for priming the Spectra, citrate reaction, and hypovolemia due to blood drawn for laboratory testing and fluid shifts at the beginning of the procedure. Hypovolemia was ultimately determined to be the most likely etiology. A rinseback was performed into a transfer bag, and the cells were sent to the laboratory for analysis of CD34+ cell yield, volume reduction, and cryopreservation. An adequate number of PBSC were recovered to permit successful autologous transplantation. The ability to recover PBSC from the Spectra white blood cell collection set allowed the patient to avoid undergoing another PSCC. In procedures involving small children, the blood volume drawn for preprocedure testing should be limited to less than 10% of the patient's total blood volume, and the RBC prime should at a minimum replace the entire extracorporeal volume. If the procedure must be terminated early, sufficient PBSC may be recoverable from the blood in the apheresis instrument.

Identification of DEIN, a Novel Gene with High Expression Levels in Stage IVS Neuroblastoma

Neuroblastoma at stage IVS, defined by dissemination to specific tissues and age <1 year at diagnosis, regularly follows spontaneous regression without cytotoxic treatment. To uncover the molecular characteristics of this subtype, Serial Analysis of Gene Expression (SAGE) profiles from stage IVS and fatal stage IV tumors were compared. A SAGE tag (GCAACTTAAC) was detected that was overrepresented in stage IVS disease and that had no reliable match in current National Center for Biotechnology Information databases of SAGE profiles, thus pointing to a novel gene. The corresponding gene, which maps to chromosome 4q33-34, was identified using a modified 3'- and 5'-rapid amplification of cDNA ends PCR and was designated as DEIN (differentially expressed in neuroblastoma). The gene comprises five transcript variants and its sequence overlaps with expressed sequences of the yet uncharacterized UniGene cluster Hs.61435. DEIN exhibits nucleotide sequence conservation over a broad range of species with an overall homology of 65% between human and mouse. As none of the predicted amino acid sequences is homologous to known proteins, it remains to be determined whether DEIN represents a coding or noncoding RNA. Northern blot analysis and semiquantitative reverse transcription-PCR showed high DEIN expression in neuroblastoma, whereas expression was absent or weak in most normal adult tissues. Analysis of 121 primary neuroblastomas by real-time reverse transcription-PCR revealed a strong association with age at diagnosis <1 year and particularly with stage IVS disease (both P < 0.001). The characteristic expression pattern of DEIN suggests a specific role of this gene in the unique biology of stage IVS tumors and may help to molecularly define this special subtype of neuroblastoma.

Continuous veno-venous haemodiafiltration in an infant with a stage IVs neuroblastoma and acute renal failure

Continuous veno-venous haemodiafiltration in an infant with a stage IVs neuroblastoma and acute renal failure

Microdontia after chemotherapy in a child treated for neuroblastoma

Chemotherapy used on paediatric oncology patients often causes disturbances in dental development. Aim of this case report is to present the late effects of chemotherapy on dental development in a patient treated for neuroblastoma at early age. Case report. This paper presents a female patient treated at early age with surgery and chemotherapy for a neuroblastoma (stage IVS) in the right thorax and massive liver metastases. The examination of the patient at age 11.7 years showed microdontia of six teeth. In three of them size and form of the crown were affected, while in the other three the size was reduced but the form was not affected. Chemotherapy on children treated for neuroblastoma can adversely influence tooth development. This has to be taken into consideration by the dentist when monitoring the development of the dentition and occlusion.