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Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high‐risk neuroblastoma (HR‐NB) before myeloablative therapy (MAT) and immunotherapy with anti‐GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR‐NB included MYCN‐nonamplified 4N diagnosed at age ≥18 months and MYCN‐amplified 4N. Among 34 MYCN‐nonamplified high‐risk patients, 20 are relapse‐free 1.5+ to 37.5+ (median 12.5+) years post‐diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post‐MAT, 8 post‐mAbs) relapsed (all soft tissue). Of 15 MYCN‐amplified 4N patients, 7 are relapse‐free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN‐nonamplified HR‐NB; small numbers prevented these analyses for MYCN‐amplified patients. The two patients with intermediate‐risk 4N (14‐months‐old) are relapse‐free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN‐nonamplified 4N. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15–25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1–3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors. [ABSTRACT FROM AUTHOR]

Anti‐GD2 monoclonal antibodies (mAb) improve the prognosis of high‐risk neuroblastoma (HR‐NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second‐line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti‐GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long‐term survival in this vulnerable age group. Thirty‐three HR‐NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized‐3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb‐related long‐term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post‐mAb treatments included chemotherapy, radiotherapy, and anti‐NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse‐free post‐mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti‐GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2/cycle) than 3F8, dinutuximab, and dinutuximab beta (70‐100 mg/m2/cycle). HR‐NB in infants proved to be highly curable. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence to suggest that the more distal a penetrating colonic injury, the poorer its expected outcome, prompting consideration of diversion rather than anastomosis when faced with left colonic injury. The clinical outcomes of penetrating colonic trauma in relation to their anatomical location within the colon were reviewed. Methods: A review was performed over eight years (2012—2020) of all patients over 18 years who had sustained penetrating colon injury and presented to our trauma centre in South Africa. Direct comparison was made between right colon vs left colon injuries. Results: A total of 450 patients were included; right colon: 260, left colon: 190. Gunshots predominated in the right colon, and the PATI was higher in this group. There were minimal differences in admission physiology and blood gas parameters between groups, but higher damage control surgery and ICU admission rates for the right colon group. There were similar rates of primary repair, anastomosis, and stoma between groups. Leak rates were no different between the two groups, and although overall complication rates were higher for the right colon, there was no difference with regard to gastro-intestinal and other complications, nor for mortality. While regression analysis did identify PATI to be a risk factor for overall complications and mortality, it failed to do so for anastomotic leak. Conclusion: Our study did not demonstrate any difference in anastomotic leak rates or mortality between right vs left colonic injury. We recommend that all colonic injuries should be treated on their own merit, balanced against the patient's condition, regardless of anatomical location within the colon. [ABSTRACT FROM AUTHOR]

Background: qSOFA has been proposed as a prognostic tool in patients with sepsis. This study set out to assess the sensitivity of several scores, namely: the pre-ICU qSOFA, the qSOFA with lactate (qSOFA L), SIRS score, qSOFA + SIRS score (qSIRS) and qSIRS with lactate (qSIRS L) in predicting in-hospital mortality in patients with surgical sepsis as well as the sensitivity of these scores in predicting high-grade sepsis. The secondary aim was to determine which of these scores is best suited to predict high-grade surgical sepsis. Methods: This was a retrospective cohort study that was conducted between December 2012 and August 2017 in a public metropolitan surgical service. Data from patients aged > 13 years, who were admitted to the hospital and who had an emergency surgical procedure for source control were retrieved from a prospectively maintained hybrid electronic database. The qSOFA, qSOFA plus lactate (qSOFA L), SIRS and qSOFA + SIRS (qSIRS), as well as the qSIRS plus lactate (qSIRS L), were calculated for each patient. A lactate level that was greater than 2mmol/L was deemed to be a positive finding. Any score ≥2 was deemed to be a positive score. The outcome measure was in-hospital mortality. The prognostic value of qSOFA, qSOFA L, SIRS, qSIRS and qSIRS L was studied. Receiver operating characteristic analyses were performed to determine the area under the curve (AUC), sensitivity, specificity and positive and negative likelihood ratios for positive qSOFA, qSOFA L, SIRS, qSIRS, and qSIRS L. Contingency tables were used to calculate the sensitivity, specificity, PPV and NPV for predicting severe or high-grade surgical sepsis. Results: There were a total number of 1884 patients in the sample group of whom 855 were female (45.4%). The median patient age was 36 years (IQR 23–56). A total of 1489 patients (79%) were deemed to have high-grade sepsis based on an advanced EGS AAST grading, whilst 395 patients (21%) had low-grade sepsis. A total of 71 patients died (3.8%). Of these patients who died, 67 (94.4%) had high-grade sepsis and 4 (5.6%) had low-grade sepsis. The mortality rate in the high-grade sepsis group was 4.5%, whilst the mortality rate in the low-grade sepsis group was 1%. The scores with the greatest accuracy in predicting mortality were qSIRS (AUROC 0.731, 95% CI 0.68–0.78), followed by SIRS (AUROC 0.70, 95% CI 0.65–0.75). The qSOFA and qSOFA L were the least accurate in predicting mortality (AUROC 0.684, 95% CI 0.63–0.74 for both). The addition of lactate had no significant effect on the accuracy of the five scores in predicting mortality. Patients with a qSOFA ≥ 2 have an increased risk of dying (OR 5.8), as do patients with a SIRS score ≥2 (OR 2.7). qSIRS L had the highest sensitivity (69%) in predicting the presence of high-grade surgical sepsis, followed by qSIRS (65.5% sensitivity). qSOFA showed a very low sensitivity of only 4.5% and a high specificity of 99.2%. The addition of lactate to the score marginally improved the sensitivity. Lactate of 2mmol/L or more was also an independent predictor of high-grade sepsis. Conclusion: The qSIRS score is most accurate in predicting mortality in surgical sepsis. The qSOFA score is inferior to both the SIRS and the qSIRS scores in predicting mortality. The qSIRS score with the addition of lactate to the qSIRS score made it the most sensitive score in predicting high-grade surgical sepsis. [ABSTRACT FROM AUTHOR]

Introduction: This study is a five-year follow-up of previously published review of the trauma workload at our institution. It aims to provide evidence about the quality of trauma care delivered by a major academic trauma service in South Africa to provide a temporal analysis of trauma trends in the city of Pietermaritzburg.Materials and methods: All trauma patients admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS) for the period December 2012-April 2018 were retrieved from the Hybrid Electronic Medical Registry (HEMR) for analysis.Results: Over the five-year period, a total of 8722 trauma patients were admitted to Grey's Hospital. There were 7242 (83.0%) males. The average age was 29.66 years. A total of 1719 (19.7%) patients less than 19 years of age, 377 (4.3%) older than 60 years of age and 1480 (17.0%) female patients were admitted following trauma. Table 3 breaks down the mechanism of trauma. A total of 5027 patients sustained blunt trauma (57.6%), and 3334 (38.5%) sustained penetrating trauma. A total of 4808 patients sustained intentional trauma implying that 55.1% of all trauma was secondary to grievous bodily harm or assault either in the form of a stab wound or GSW or of an assault. There was a total of 2232 road traffic-related incidents, of which 37.9% (845) were pedestrian victims. The mortality rate for all trauma admissions was 4.5% (396). Of these 396 deaths, 64 (16.2%) were classified at the morbidity and mortality conference as being avoidable.Conclusions: The HEMR has allowed us to track the burden of trauma presenting to our institution over a five-year period. This confirms previous studies over shorter time periods from our institution. The pattern of trauma has remained consistent, and the previously described high levels show no sign of decreasing. Interventions to try and reduce this burden are urgently required. [ABSTRACT FROM AUTHOR]

Adult‐onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult‐onset neuroblastoma. Anti‐GD2 immunotherapy is now standard therapy in children with high‐risk neuroblastoma; however, its use has not been reported in adults. Forty‐four adults (18–71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN‐amplification. In the 11 patients with locoregional disease, 10‐year progression‐free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti‐GD2 antibodies, mouse or humanized 3F8. Antibody‐related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5‐year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10‐year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult‐onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long‐term survival. Anti‐GD2 immunotherapy was well tolerated and might be beneficial. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to review the trauma workload and operative exposure in a major South African trauma center and provide a comparison with contemporary experience from major military conflict. Materials and methods: All patients admitted to the PMTS following trauma were identified from the HEMR. Basic demographic data including mechanism of injury and body region injured were reviewed. All operative procedures were categorized. The total operative volume was compared with those available from contemporary literature documenting experience from military conflict in Afghanistan. Operative volume was converted to number of cases per year for comparison. Results: During the 4-year study period, 11,548 patients were admitted to our trauma center. Eighty-four percent were male and the mean age was 29 years. There were 4974 cases of penetrating trauma, of which 3820 (77%) were stab wounds (SWs), 1006 (20%) gunshot wounds (GSWs) and the remaining 148 (3%) were animal injuries. There were 6574 cases of blunt trauma. The mechanism of injuries was as follows: assaults 2956, road traffic accidents 2674, falls 664, hangings 67, animal injuries 42, sports injury 29 and other injuries 142. A total of 4207 operations were performed. The volumes per year were equivalent to those reported from the military surgical literature. Conclusion: South Africa has sufficient burden of trauma to train combat surgeons. Each index case as identified from the military surgery literature has a sufficient volume in our center. Based on our work load, a 6-month rotation should be sufficient to provide exposure to almost all the major traumatic conditions likely to be encountered on the modern battlefield. [ABSTRACT FROM AUTHOR]

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors ( NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m−2 day−1 after a loading dose of 100-200 mg m−2 on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings ( i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; ( ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and ( iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable. [ABSTRACT FROM AUTHOR]

The insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors. [ABSTRACT FROM AUTHOR]

BACKGROUND Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging. METHODS The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma. RESULTS A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years). CONCLUSIONS Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative. Cancer 2015. © 2015 American Cancer Society. Cancer 2015;121:2090-2096. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Antibody-based immunotherapy has proven efficacy for patients with high-risk neuroblastoma. However, despite being the most efficient tumoricidal effectors, T cells are underutilized because they lack Fc receptors. Using a monovalent single-chain fragment (ScFv) platform, we engineered tandem scFv bispecific antibodies (BsAbs) that specifically target disialoganglioside (GD2) on tumor cells and CD3 on T cells. Structural variants of BsAbs were constructed and ranked based on binding to GD2, and on competency in inducing T-cell-mediated tumor cytotoxicity. In vitro thermal stability and binding measurements were used to characterize each of the constructs, and in silico molecular modeling was used to show how the orientation of the variable region heavy (VH) and light (VL) chains of the anti-GD2 ScFv could alter the conformations of key residues responsible for high affinity binding. We showed that the VH-VL orientation, the (GGGGS)3 linker, disulfide bond stabilization of scFv, when combined with an affinity matured mutation provided the most efficient BsAb to direct T cells to lyse GD2-positive tumor cells. In vivo, the optimized BsAb could efficiently inhibit melanoma and neuroblastoma xenograft growth. These findings provide preclinical validation of a structure-based method to assist in designing BsAb for T-cell-mediated therapy. [ABSTRACT FROM AUTHOR]

The article emphasizes the importance of discussing with patients the risks associated with the peri-operative surgical process. Topics discussed include the mortality risk relating to the induction of anesthesia, importance of harm and benefit perception to health decision making, need of pre-operative testing to reduce peri-operative risk, key objective of peri-operative risk assessment, and risk associated with peri-operative pharmacological interventions.

Anti-GD2 murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-GD2 antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13- cis-retinoic acid. Study endpoints were: ( i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and ( ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF ( p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-GD2 immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors. [ABSTRACT FROM AUTHOR]

BACKGROUND The authors exploited a large database to investigate the outcomes of patients with high-risk neuroblastoma in the contemporary era. METHODS All patients with high-risk neuroblastoma aged <12 years who were treated during induction at the authors' institution from 2000 through 2011 were studied, including 118 patients with MYCN-amplified [ MYCN(+)] disease and 127 patients aged >18 months with MYCN-nonamplified [ MYCN(−)] stage 4 disease. RESULTS A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event-free survival (EFS) ( P < .001) and overall survival (OS) ( P < .001) compared with a partial response or less. Patients with MYCN(+) and MYCN(−) disease had similar rates of CR/VGPR to induction ( P = .366), and those with MYCN(+) and MYCN(−) disease who attained a CR/VGPR had similar EFS ( P = .346) and OS ( P = .542). In contrast, only MYCN(+) patients had progressive disease as a response to induction ( P < .001), and early death from progressive disease (<366 days after diagnosis) was significantly more common ( P < .001) among those with MYCN(+) disease. Overall, among patients who had a partial response or less, MYCN(+) patients had significantly inferior EFS ( P < .001) and OS ( P < .001) compared with MYCN(−) patients, which accounted for the significantly worse EFS ( P = .008) and OS ( P = .002) for the entire MYCN(+) cohort versus the MYCN(−) cohort. CONCLUSIONS Patients with MYCN(−), high-risk neuroblastoma display a broad, continuous spectrum with regard to response and outcome, whereas MYCN(+) patients either have an excellent response to induction associated with good long-term outcome or develop early progressive disease with a poor outcome. This extreme dichotomy in the clinical course of MYCN(+) patients points to underlying biologic differences with MYCN(+) neuroblastoma, the elucidation of which may have far-reaching implications, including improved risk classification at diagnosis and the identification of targets for treatment. Cancer 2014;120:2050-2059. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy. [Copyright &y& Elsevier]

Background: Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2 ) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES.Methods: Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8.Results: PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD-3F8 (P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external-beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation (P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES.Conclusions: Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES. METHODS Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8. RESULTS PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD-3F8 ( P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external-beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation ( P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES. CONCLUSIONS Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy. Cancer 2013;119:2789-2795. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors report a retrospective analysis of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB. METHODS: Treatment comprised ifosfamide (2000 mg/m2 daily for 5 days), carboplatin (500 mg/m2 daily for 2 days), and etoposide (100 mg/m2 daily for 5 days). Patients who had poor hematologic reserve (platelet count <100,000/μL) from previous therapy received peripheral blood stem cells (PBSCs) after HD-ICE. Disease status before and after HD-ICE was defined according to International Neuroblastoma Response Criteria (expanded to include 123I-metaiodobenzylguanidine findings). Publications that were informative about ICE for NB were reviewed. RESULTS: Seventy-four patients received 92 cycles of ICE, including 37 patients who received PBSC rescue. Grade 3 toxicities were rare: 1-3 patients had encephalopathy, mucositis, or gastroenteritis. Bacteremia was documented in 24 of 92 cycles (26%). The absolute neutrophil count reached 500/μL on day 17-30 (median, day 22) in patients who had satisfactory hematologic reserve. Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory NB, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy ( P = .005). In the literature, patients received ICE at lower dosages and achieved major response rates >36% in phase 1 and 2 studies (in which less comprehensive staging evaluations were used) that involved resistant NB and >70% in induction for newly diagnosed NB. CONCLUSIONS: HD-ICE is appealing as salvage treatment or consolidative therapy because of its anti-NB activity and the low risk of major nonhematologic toxicity. PBSC support is unnecessary for patients who had intact hematologic reserve. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

The BMI1 gene is overexpressed in -90% of human neuroblastomas. However, little is known about the regulation of BMI1 expression. Using microarray and immunohistochemical analysis, we show that BMI1 expression correlated with MYCN levels in MYCN-amplified human neuroblastomas, and with MYC levels in the MYCN-nonamplified group. We further demonstrated that BMI1 is a direct target gene of MYCN/MYC in 3 neuroblastoma cell lines: BE (2)-C, LAN1, and SH-SY5Y. Overexpression of MYCN or MYC transactivated the BMI1 promoter and up-regulated BMI1 gene expression, shRNA-mediated knockdown of MYCN or MYC decreased BMI1 gene expression. Chromatin immunoprecipitation and point-mutation assays revealed that both MYCN and MYC bind to the E-box within the BMI1 promoter. Overexpression of BMI1, MYCN, and MYC independently increased both cell proliferation and tumor growth. Conversely, specific inhibition of BMI1, MYCN, and MYC decreased tumor cell proliferation and tumor growth. Interestingly, BMI1 suppression in MYCN/ MYC-overexpressing cells resulted in significantly greater inhibition compared to that in mock-transduced and parental cells. Our results indicate that MYCN and MYC regulate BMI1 gene expression at the transcriptional level and that dysregulation of the BMI1 gene mediated by MYCN or MYC overexpression, confers increased cell proliferation during neuroblastoma genesis and tumor progression. [ABSTRACT FROM AUTHOR]

Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G2 cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14 ARF genomic status. Four of four p53 mutant lines and three of five MDM2/p14 ARF abnormal lines were defective in G1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G1 checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G2 checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G1 checkpoints. [ABSTRACT FROM AUTHOR]

The article provides information on a retrospective study which determined statistically the likelihood of response to a given salvage therapy in different clinical subsets of pediatric patients with chemoresistant neuroblastoma (NB). A background on the clinical characteristics of patients treated with high-dose cyclophosphamide, topotecan, and vincristine (HD-CTV) is given. A discussion on the research findings is detailed.

Methionine starvation can modulate gene methylation, cell cycle transition and pathways related to survival following DNA damage. Methionine depletion by recombinant methioninase (rMETase) may have in vitro and in vivo efficacy against neuroblastoma (NB), especially when combined with chemotherapeutic drugs. rMETase from Pseudomonas putida was produced in Escherichia coli and purified by ion-exchange chromatography. rMETase alone inhibited the proliferation of 15/15 NB cell lines in vitro. Among these 15 cell lines, only 66N demonstrated rMETase-induced apoptosis. rMETase alone suppressed LAN-1 and NMB-7 xenografts ( p < 0.01) and no toxicities were noted other than reversible weight loss. In vitro efficacy experiments combining rMETase and chemotherapeutic agents were carried out using SK-N-LD and SK-N-BE (1)N established at diagnosis, as well as LAN-1, SK-N-BE (2)C and NMB-7 established at relapse. Microtubule depolymerization agents including vincristine, vinorelbine, vinblatine and mebendazole showed synergism when tested in combination with rMETase in all 5 cell lines. Among DNA damaging agents, synergy with rMETase was observed only in cell lines established at diagnosis and not at relapse. Cell cycle analysis showed that rMETase arrested G2 phase and not M phase. In vivo efficacy experiments using LAN-1 and NMB-7 xenografts showed that rMETase rendered vincristine more effective than vincristine alone in tumor growth suppression ( p < 0.001). In conclusion, methionine depletion inhibited NB proliferation and arrested tumor cells at G2 phase. rMETase synergized with microtubule depolymerization agents. Moreover, synergism between rMETase and DNA damaging agents was dependent on whether cell lines were established at diagnosis or at relapse. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Polysialic acid (PSA) is highly expressed in many human cancers, including neuroblastoma (NB), and is critical for cellular adhesion, neuronal migration and tumor metastasis. The key enzyme responsible for PSA synthesis is sialyltransferase STX (ST8SiaII). Using quantitative RT-PCR we ( i) studied STX expression in 39 NB tumors and 8 cell lines and ( ii) examined its potential clinical utility as an early response marker in the bone marrows of the entire cohort of 136 high-risk NB patients treated with an immunotherapy protocol utilizing anti-GD2 antibody 3F8 and GM-CSF. Based on the quantitation of 24 normal marrow and peripheral blood samples, a normalized STX transcript value below the mean + 2SD was defined as negative. Sensitivity of this assay was 1 NB cell in 10 [ABSTRACT FROM AUTHOR]