Medicine › Neurology

Neuroblastoma Research and Treatments

Works Count: 45652

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Description

This cluster of papers represents a comprehensive exploration of neuroblastoma, covering topics such as genetic mutations (including ALK and MYCN), risk classification, staging systems, immunotherapy, and genomic analysis. The research also delves into therapy strategies and prognosis for patients with neuroblastoma.

Keywords

Neuroblastoma; ALK; Genomic; MYCN; Therapy; Risk Classification; Immunotherapy; Genetic Mutations; Staging System; Prognosis

Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN

2000-05-01

Tal Teitz , Tie Wei , Marcus B. Valentine +7 more

Histology for Pathologists

1992-08-01

Stephen S. Sternberg

Bone marrow, S.N.Wickramasinghe adipose tissue, John J. Brooks and Patricia M.Perosio bone, A. Marion Gurley and Sanford I.Roth skeletal muscle, R Reid Heffner Jr myofibroblast, Walte Schurch et al central … Bone marrow, S.N.Wickramasinghe adipose tissue, John J. Brooks and Patricia M.Perosio bone, A. Marion Gurley and Sanford I.Roth skeletal muscle, R Reid Heffner Jr myofibroblast, Walte Schurch et al central nervous system, Gregory N. Fuller and Peter C. Burger peripheral nervous system, Carlos Ortis Hidalgo and Roy O'weller blood vessels, Patrick J.Gallagher normal heart, Margaret E. Billingham reactive lymph nodes, Paul van der Valk and Chris J.L.M. Meijer spleen, J.H.J.M. van Kricken and J.te Velde thymus, Saul Suster and Juan Rosai pituitary and sellar region, P.J. Pernicone et al thyroid, Virginia A. LiVolsi parathyroid glands, Graziella M. Abu Jawdeh and Sanford I.Roth adrenal gland, J.Aidan Carney neuroendocrine system, Ronald A. DeLellis and Yogeshwar Dayal paraganglia, Arthur S. Tischler noral skin, Carlos Urmacher nail, Julian Sanchez Conejo-Mir periodontiu, Minor salivary glands and maxillary sinus, Kenneth D. McClatchey larynx and pharynx, Robert E. Fechner major salivary glands, Fernando Martinez Madrigal and Christian Micheau lungs, Thomas V. Colby and Samuel A. Yousem serous membranes, Darryl Carter et al esophagus, Franco G. DeNardi and Robert H. Riddell stomach, David A. Owen small intestine, Glenn H.Segal and Robert E. Petras colon, Douglas S. Levine and Rodger C. Haggitt vermiform appendix, H. Glenn et al anal canal, Claus Fenger liver, N. Swan et al gallbladder and extrahepatic biliary system, Henry F. Frierson Jr pancreas, James E Oertel et al pediatric kidney, J. Bruce Beckwith adult kidney, urinary bladder and ureter, Victor E. Reuter penis, Jose Barreto et al testis and excretory duct system, Thomas D.Trainer prostate, John E. McNeal ovary, Philip B. Clement uterus, cervix and fallopian tube, Michael R Hendrickson and Richard Kempson placenta, Steven H. Lewis and Kurt Benirschke vulva, Edward J. Wilkinson and Nancy Hardt vagina, Stanley J. Robboy et al breast, Kenneth S. McCarty, Jr and J. Allen Tucker normal eye and ocular adnexa, Mark W. Scroggs and Gordon K. Klintworth ear, Leslie Michaels.

Descriptive physical oceanography: an introduction

1983-01-01

George L. Pickard

Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture.

1973-11-01

June L. Biedler , Lawrence Helson , Barbara A. Spengler

Summary Continuous cell lines, SK-N-SH and SK-N-MC, were established in cell culture from human metastatic neuroblastoma tissue and maintained in vitro for 1 to 2 years. SK-N-SH comprises two morphologically … Summary Continuous cell lines, SK-N-SH and SK-N-MC, were established in cell culture from human metastatic neuroblastoma tissue and maintained in vitro for 1 to 2 years. SK-N-SH comprises two morphologically distinctive cell types, a small spiny cell and a large epithelioid cell. SK-N-MC is composed of small fibroblast-like cells with scant cytoplasm. In monolayer culture both cell lines form disoriented growth patterns and reach high saturation densities. Population-doubling times were 44 and 32 hr for SK-N-SH and SK-N-MC, respectively. Inoculum levels of 10 7 cells of both lines produced tumors confirmed by histopathological examination, at frequencies of 30 to 40% in cheek pouches of conditioned Syrian hamsters. SK-N-SH cells are characterized by high dopamine-β-hydroxylase activity while SK-N-MC cells have no detectable activity. However, for SK-N-MC but not SK-N-SH, the presence of intracellular catecholamine was indicated by formaldehyde-induced fluorescence. The lines are near-diploid with several chromosomal markers; SK-N-MC cells contain double- minute chromosomes. Growth, biochemical, and cytogenetic properties confirmed that the lines comprise malignant cells of neurogenic origin.

Histopathologic Prognostic Factors in Neuroblastic Tumors: Definition of Subtypes of Ganglioneuroblastoma and an Age-Linked Classification of Neuroblastomas

1984-08-01

Hiroyuki Shimada , Jane Chatten , William A. Newton +5 more

Histopathologic prognostic factors of 295 pretreatment tumors of a total 641 neuroblastomas and ganglioneuroblastomas were studied with the use of the following proposed tumor classification. The tumors were divided into … Histopathologic prognostic factors of 295 pretreatment tumors of a total 641 neuroblastomas and ganglioneuroblastomas were studied with the use of the following proposed tumor classification. The tumors were divided into 2 groups: stroma-poor (235 cases) and stroma-rich (60 cases) according to their organizational pattern (stromal development). The stroma-poor group was classified further into 2 subgroups: favorable stroma-poor (84% survival) and unfavorable stroma-poor (4.5% survival) according to the patient's age at diagnosis, degree of maturation, and nuclear pathology [mitosis-karyorrhexis index (MKI)] of the neuroblastic cells. The stroma-rich group was further classified into 3 subgroups: well differentiated (100% survival), intermixed (92% survival), and nodular (18% survival) on the basis of morphology of the immature element in the tumor tissue without regard to patient's age or quantitative maturation. Favorable stroma-poor and well-differentiated and intermixed stroma-rich groups seem to make good prognosis groups (87% survival), which show gradual progression along a maturational sequence according to the age of the patient. Unfavorable stroma-poor and nodular stroma-rich groups form poor prognosis groups (7% survival) and show morphological evidence of malignant or aggressive behavior, such as inappropriate immaturity for age, higher MKI, and gross nodule formation by immature neuroblasts.

The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen

1984-12-01

Alan L. Schechter , David F. Stern , Lalitha Vaidyanathan +4 more

Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin

1985-01-01

Towia A. Libermann , Harris R. Nusbaum , Nissim Razon +7 more

Experience with the Use of High-Dose Interleukin-2 in the Treatment of 652 Cancer Patients

1989-10-01

Steven A. Rosenberg , Michael T. Lotze , James Chih‐Hsin Yang +4 more

We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease … We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease for which no standard effective therapy existed, and 56 patients were treated in the absence of evaluable disease in the adjuvant setting. IL-2 was administered either alone (155 patients) or in conjunction with activated immune cells such as lymphokine activated killer (LAK) cells (214 patients) or tumor infiltrating lymphocytes (TIL) (66 patients), with other cytokines such as alpha interferon (a-IFN)(128 patients) or tumor necrosis factor (TNF)(38 patients), with monoclonal antibodies (32 patients), or with the chemotherapeutic agent cyclophosphamide (19 patients). Initial results with the treatment of high-dose IL-2 alone or in conjunction with LAK cells have indicated that objective regressions of cancer can be achieved in 20% to 35% of patients with selected advanced metastatic cancers. Although most responses have been seen in patients with metastatic renal cell cancer, melanoma, colorectal cancer, and non-Hodgkin's lymphoma, many histologic types of cancer have not been treated in significant numbers. These regressions can be durable; of 18 patients achieving a complete response, ten have not experienced recurrence at intervals from 18 to 52 months. Although combinations of IL-2 with TNF do not appear to result in increased responses, there is a suggestion in our initial phase I studies that the combination of a-IFN and IL-2 is more effective than the administration of cytokine alone and this combination deserves further study. Similarly the adoptive transfer of TIL in conjunction with IL-2 also appears to be more effective than the use of IL-2 alone. The toxic side effects in patients treated with high-dose IL-2 are presented and include malaise, nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Treatment-related deaths were seen in 1% of all treatment courses and in 1.5% of patients. These studies demonstrate that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.

Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers

1997-08-01

Mourad Kaghad , H Bonnet , Annie Yang +7 more

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Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

2001-01-01

J I Johnson , Shannon Decker , Daniel Zaharevitz +7 more

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with … An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign

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Identification of ALK as a major familial neuroblastoma predisposition gene

2008-08-24

Yaël P. Mossé , Marci Laudenslager , Luca Longo +7 more

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Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour

1983-09-01

Manfred Schwab , Kari Alitalo , Karl-Heinz Klempnauer +6 more

A proposed staging for children with neuroblastoma.Children's cancer study group A

1971-02-01

Audrey E. Evans , Giulio J. D’Angio , Judson Randolph

A clinical staging of patients with neuroblastoma is proposed. Such staging is desirable to aid in estimating the prognosis and to be able to evaluate the efficacy of differing therapeutic … A clinical staging of patients with neuroblastoma is proposed. Such staging is desirable to aid in estimating the prognosis and to be able to evaluate the efficacy of differing therapeutic regimens by analyzing results obtained in comparable groups of patients. That the suggested staging is practical is illustrated by the ease with which 100 children with neuroblastoma, entered in previous studies by Children's Cancer Study Group A, were staged using the criteria described. Short-term survival data of this small sample demonstrated, in addition, that the proposed staging appears to be of help in estimating the prognosis. Also proposed is a list of investigations which aid in accurate staging.

Cellular Oncogenes and Multistep Carcinogenesis

1983-11-18

Hartmut Land , Luis F. Parada , Robert A. Weinberg

Two dozen cellular proto-oncogenes have been discovered to date through the study of retroviruses and the use of gene transfer. They form a structurally and functionally heterogeneous group. At least … Two dozen cellular proto-oncogenes have been discovered to date through the study of retroviruses and the use of gene transfer. They form a structurally and functionally heterogeneous group. At least five distinct mechanisms are responsible for their conversion to active oncogenes. Recent work provides experimental strategies by which many of these oncogenes, as well as oncogenes of DNA tumor viruses, may be placed into functional categories. These procedures may lead to definition of a small number of common pathways through which the various oncogenes act to transform cells.

The International Neuroblastoma Pathology Classification (the Shimada system)

1999-07-15

Hiroyuki Shimada , Inge M. Ambros , Louis P. Dehner +7 more

The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features … The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma).A total of 227 cases were reviewed. Consensus diagnoses from morphologic features (criteria described separately) based on five of six or six of six agreements by the reviewer pathologists were used for prognostic analysis. Prognostic effects of morphology, both individual and in combination, taken in conjunction with age (Shimada classification, histologic grade, and risk group), were analyzed.Approximately 99% of cases (224 of 227) had consensus diagnoses for categorization: neuroblastoma (Schwannian stroma-poor), 190 cases; ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases; ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case; ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94 cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus: low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical analysis demonstrated that the Shimada classification system (90% consensus; 3-year event free survival: 85% for the group with favorable histology and 41% for the group with unfavorable histology; P = 0.31 x 10(-9)) had a significantly stronger prognostic effect than individual features and other combinations.The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs.

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

2008-10-01

Isabelle Janoueix‐Lerosey , Delphine Lequin , Laurence Brugières +7 more

Amplification of N- myc in Untreated Human Neuroblastomas Correlates with Advanced Disease Stage

1984-06-08

Garrett M. Brodeur , Robert C. Seeger , Manfred Schwab +2 more

A domain of DNA designated N-myc is amplified 20- to 140-fold in human neuroblastoma cell lines but not in cell lines from other tumor types. N-myc has now been found … A domain of DNA designated N-myc is amplified 20- to 140-fold in human neuroblastoma cell lines but not in cell lines from other tumor types. N-myc has now been found to be amplified in neuroblastoma tissue from 24 of 63 untreated patients (38 percent). The extent of amplification appears to be bimodal, with amplification of 100- to 300-fold in 12 cases and 3- to 10-fold in 10 others. Amplification was found in 0 of 15 patients with stage 1 or 2 disease, whereas 24 of 48 cases (50 percent) with stage 3 or 4 had evidence of N-myc amplification. These data indicate that N-myc amplification is a common event in untreated human neuroblastomas. Furthermore, N-myc amplification is highly correlated with advanced stages of disease (P less than 0.001) and with the ability to grow in vitro as an established cell line, both of which are associated with a poor prognosis.

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

2000-04-15

Giannoula Klement , Sylvain Baruchel , Janusz Rak +5 more

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or … Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months.

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Oncogenic mutations of ALK kinase in neuroblastoma

2008-10-01

Yuyan Chen , Junko Takita , Young Lim Choi +7 more

Targeted expression of MYCN causes neuroblastoma in transgenic mice

1997-06-01

William A. Weiss , Kenneth Aldape , Gayatry Mohapatra +2 more

Relations between the central Nervous System and the peripheral organs

1954-07-01

Erich v. Holst

Activating mutations in ALK provide a therapeutic target in neuroblastoma

2008-10-01

Rani E. George , Takaomi Sanda , Megan Hanna +7 more

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Neuroblastoma: biological insights into a clinical enigma

2003-02-28

Garrett M. Brodeur

Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185

1986-06-01

Cornelia I. Bargmann , Mien‐Chie Hung , Robert A. Weinberg

Pathology of Tumors of the Nervous System.

1964-09-01

R. B. Richter

There is no reason why this, the second edition of the most definitive contemporary treatise on nervous system tumors written in English, will not have the same welcome reception it … There is no reason why this, the second edition of the most definitive contemporary treatise on nervous system tumors written in English, will not have the same welcome reception it earned at its debut five years ago. The book is a wholly representative statement of modern British work in the field, comparable to its companion volume on neuropathology by the late Professor Greenfield and his collaborators. For those few readers not familiar with the first edition, it may be stated briefly that the book contains ample descriptions of all the commonly recognized neoplasms of the nervous system, including those of developmental and of secondarily invasive origin as well as the primary tumors of meningeal, vascular, and neuroectodermal derivation. The biological characteristics of the respective tumors are given adequate consideration, and the classification employed by the authors, a modified but not overly simplified version of the cytogenetic schema of Bailey and

Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma.

1987-07-01

S P Staal

A previous report described the isolation of a directly transforming retrovirus, AKT8, from a spontaneous thymoma of an AKR mouse. The AKT8 provirus has now been molecularly cloned from a … A previous report described the isolation of a directly transforming retrovirus, AKT8, from a spontaneous thymoma of an AKR mouse. The AKT8 provirus has now been molecularly cloned from a transformed, nonproducer cell line. The virus genome contains both viral and nonviral, cell-related sequences; the nonviral sequence has been designated v-akt, the presumed viral oncogene of the AKT8 virus. This gene lacks homology to the 16 other oncogenes tested. The cloned provirus has undergone a partial deletion, during cell passage in vitro, that prevents direct demonstration of the transforming ability of this molecular clone. Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned. A survey of 225 human tumors for changes involving AKT1 led to the discovery of a 20-fold amplification of this gene in one of the five gastric adenocarcinomas tested. The results demonstrate that AKT8 has the characteristic structure of a directly transforming retrovirus and that it contains a gene derived from highly conserved cellular sequences that may be involved in the pathogenesis of some human malignancies.

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Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor

1986-01-01

Tadashi Yamamoto , Shuntaro Ikawa , Tetsu Akiyama +5 more

Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment.

1993-08-01

G M Brodeur , Jon Pritchard , Frank Berthold +7 more

PURPOSE AND METHODS: Based on preliminary experience, there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, … PURPOSE AND METHODS: Based on preliminary experience, there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, a proposal was made to establish an internationally accepted staging system for neuroblastoma, as well as consistent criteria for confirming the diagnosis and determining response to therapy (Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A meeting was held to review experience with the INSS and INRC and to revise or clarify the language and intent of the originally proposed criteria. Substantial changes included a redefinition of the midline, restrictions on age and bone marrow involvement for stage 4S, and the recommendation that meta-iodobenzylguanidine (MIBG) scanning be implemented for evaluating the extent of disease. Other modifications and clarifications of the INSS and INRC are presented. In addition, the criteria for the diagnosis of neuroblastoma were modified. Finally, proposals were made for the development of risk groups that incorporate both clinical and biologic features in the prediction of prognosis. The biologic features that were deemed important to evaluate prospectively included serum ferritin, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH); tumor histology; tumor-cell DNA content; assessment of N-myc copy number; assessment of 1p deletion by cytogenetic or molecular methods; and TRK-A expression. RESULTS AND CONCLUSION: Modifications of the INSS and INRC made at this conference are presented. In addition, proposals are made for future modifications in these criteria and for the development of International Neuroblastoma Risk Groups.

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

2015-08-25

Navin Pinto , Mark A. Applebaum , Samuel L. Volchenboum +7 more

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare … Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

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THE METABOLISM OF TUMORS IN THE BODY

1927-03-07

Otto Warbürg , Franz Wind , Erwin Negelein

In this contribution we discuss the question of whether tumor cells in living animals can be killed off through lack of energy, and the related question of how the tumors … In this contribution we discuss the question of whether tumor cells in living animals can be killed off through lack of energy, and the related question of how the tumors are supplied with oxygen and glucose in the body.We assume it is understood that tumor cells obtain the energy required for their existence in two ways: by respiration and by fermentation.In respiration they burn organic materials to carbon dioxide and water; in fermentation they split glucose to lactic acid.All tumors so far tested behave fundamentally alike.There is no essential difference between the cancer cells of transplanted rat tumors and spontaneous tumors, sarcoma and carcinoma cells, and the tar carcinoma, and Rous sarcoma produced by filtrate.The fermentation of tumors was first found with cut pieces of tumor in vitro.I C. and G. Cori 2 demonstrated it in living animals as well.They determined the glucose and lactic acid in the axillary veins of hens having in one wing a Rous sarcoma, and found in 100 cc. of blood 23 mg.less glucose and 16 rag.more lactic acid on the tumor side than on the normal side.A corresponding experiment with a human fore-arm tumor showed in 100 cc. of blood 12 rag.less glucose and 9 rag.more lactic acid on the tumor side.In experiments on the nourishment of tumors through the blood stream, we, like Cori, determined the glucose and lactic acid in tumor veins.Our procedure differed from Cori's in that we compared tumor veins and arteries, not tumor veins and corresponding normal veins.Our differences were greater than Cori's because we went closer to 1

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MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells

2007-02-12

Carrie L. Welch , Y Chen , Raymond L. Stallings

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

2012-02-21

Jan J. Molenaar , Jan Köster , Danny A. Zwijnenburg +7 more

Whole-genome sequencing of neuroblastoma, a childhood tumour of the nervous system, shows that chromothripsis (a local shredding of chromosomes) and mutations in genes regulating neurite growth are associated with the … Whole-genome sequencing of neuroblastoma, a childhood tumour of the nervous system, shows that chromothripsis (a local shredding of chromosomes) and mutations in genes regulating neurite growth are associated with the most aggressive tumours. Whole-genome sequencing is used here to identify genetic defects in 87 people with neuroblastoma, a childhood tumour of the peripheral sympathetic nervous system. Analyses revealed few recurrent amino-acid-changing mutations, but a series of genes functioning in neuritogenesis and extension of neuronal growth cones were deleted in aggressive high-stage tumours. Chromothripsis, the localized shattering of the chromosomes, was common in high-stage tumours and was generally associated with poor prognosis. Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2,3,4,5. Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7,8,9. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.

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Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma

2010-09-29

Alice L. Yu , Andrew L. Gilman , M. Fevzi Özkaynak +7 more

Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined … Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

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Recent Advances in Neuroblastoma

2010-06-10

John M. Maris

Neuroblastoma, an embryonal cancer of the autonomic nervous system, is the most common cancer diagnosed during the first year of life. Although neuroblastoma accounts for disproportionately high morbidity and mortality … Neuroblastoma, an embryonal cancer of the autonomic nervous system, is the most common cancer diagnosed during the first year of life. Although neuroblastoma accounts for disproportionately high morbidity and mortality among childhood cancers, it has one of the highest rates of spontaneous and complete regression. The author discusses recent advances in our understanding of neuroblastoma.

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The genetic landscape of high-risk neuroblastoma

2013-01-20

Trevor J. Pugh , Olena Morozova , Edward F. Attiyeh +7 more

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Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification.

1987-10-01

Albert J. Wong , Sandra H. Bigner , Darell D. Bigner +3 more

Primary malignant gliomas from 63 patients were analyzed to determine the relationship between amplification of the gene encoding the epidermal growth factor receptor (EGFR) and expression of the corresponding mRNA. … Primary malignant gliomas from 63 patients were analyzed to determine the relationship between amplification of the gene encoding the epidermal growth factor receptor (EGFR) and expression of the corresponding mRNA. Twenty-four tumors were found to have amplified the EGFR gene and amplification of other genes occurred in three additional tumors. Hybridization with synthetic RNA probes was used to quantitate mRNA levels in situ. All 24 tumors with amplification of the EGFR gene had high levels of expression of this gene, while none of the 39 tumors without amplification had increased levels. This shows that, in human gliomas, large increases in the expression of the EGFR gene are invariably associated with alterations in gene structure.

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Hereditary cancer, oncogenes, and antioncogenes.

1985-04-01

Alfred G. Knudson

The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report

2008-12-02

Tom Monclair , Garrett M. Brodeur , Peter F. Ambros +7 more

The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging … The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging system, a new clinical staging system was required for the INRG pretreatment risk classification system.

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Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children's Oncology Group Study

2009-01-27

Katherine K. Matthay , C. Patrick Reynolds , Robert C. Seeger +6 more

PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or … PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA). PATIENTS AND METHODS Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months. Results The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean +/- SE) was 30% +/- 4% versus 19% +/- 3%, respectively (P = .04). The 5-year EFS (42% +/- 5% v 31% +/- 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(-log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% +/- 8%; for ABMT/no cis-RA, it was 41% +/- 8% [corrected]; for continuing chemotherapy/cis-RA, it was 38% +/- 7%; and for chemotherapy/no cis-RA, it was 36% +/- 7%.Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS than nonmyeloablative chemo therapy; neither myeloablative therapy with [corrected] autologous hematopoietic cell rescue nor cis-RA given after consolidation therapy significantly improved OS.

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The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report

2008-12-02

Susan L. Cohn , Andrew D.J. Pearson , Wendy B. London +7 more

Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International … Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification.The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors.Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively.By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

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THE MOLECULAR GENETICS OF CELLULAR ONCOGENES

1984-12-01

Harold Varmus

Orthologs and paralogs are two fundamentally different types of homologous genes that evolved, respectively, by vertical descent from a single ancestral gene and by duplication. Orthology and paralogy are key … Orthologs and paralogs are two fundamentally different types of homologous genes that evolved, respectively, by vertical descent from a single ancestral gene and by duplication. Orthology and paralogy are key concepts of evolutionary genomics. A ...Read More

A distinct “side population” of cells with high drug efflux capacity in human tumor cells

2004-09-20

Charlotte Hirschmann-Jax , Angela E. Foster , Gerald Wulf +5 more

A subset of stem cells, termed the “side population” (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We … A subset of stem cells, termed the “side population” (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.

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New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

2016-02-01

Dominik Sturm , Brent A. Orr , Umut H. Toprak +7 more

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Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic Acid

1999-10-14

Katherine K. Matthay , Judith G. Villablanca , Robert C. Seeger +7 more

Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with … Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival.

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Association of Multiple Copies of the N-mycOncogene with Rapid Progression of Neuroblastomas

1985-10-31

Robert C. Seeger , Garrett M. Brodeur , Harland N. Sather +4 more

Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to … Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to 300 copies) of N-myc was detected in 2 of 16 tumors in Stage II, 13 of 20 in Stage III, and 19 of 40 in Stage IV; in contrast, 8 Stage I and 5 Stage IV-S tumors all had 1 copy of the gene (P<0.01). Analysis of progression-free survival in all patients revealed that amplification of N-myc was associated with the worst prognosis (P<0.0001); the estimated progression-free survival at 18 months was 70 per cent, 30 per cent, and 5 per cent for patients whose tumors had 1, 3 to 10, or more than 10 N-myc copies, respectively. Of 16 Stage II tumors, 2 with amplification metastasized, whereas only 1 of 14 without amplification did so (P = 0.03). Stage IV tumors with amplification progressed most rapidly: nine months after diagnosis the estimated progression-free survival was 61 per cent, 47 per cent, and 0 per cent in patients whose tumors had 1, 3 to 10, or more than 10 copies, respectively (P<0.0001). These results suggest that genomic amplification of N-myc may have a key role in determining the aggressiveness of neuroblastomas. (N Engl J Med 1985; 313: 1111–6.)

Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology

2013-01-01

Jane Kovalevich , Dianne Langford

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Methods in molecular biology

1998-05-01

Philippe Métézeau

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Neuroblastoma

2007-06-01

John M. Maris , Michael D. Hogarty , Rochelle Bagatell +1 more

Neuroblastoma

2016-11-10

Katherine K. Matthay , John M. Maris , Gudrun Schleiermacher +4 more

Peripheral neuroblastic tumors: tumor biology and its implications for risk stratification

2025-06-25

Aroua Anissi Eddaibouni , Sanaa Hachimi , N. Bennani Guebessi +2 more | European Journal of Pediatrics

Phase I Study of 131 I-Metaiodobenzylguanidine With Dinutuximab ± Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial

2025-06-23

Thomas F. Cash , Araz Marachelian , Steven G. DuBois +7 more | Journal of Clinical Oncology

We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase … We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL). In part A, patients with MIBG-avid rNBL received MIBG intravenously (IV) on day 1 at 12, 15, or 18 mCi/kg per the rolling six design and dinutuximab (17.5 mg/m2 once daily) IV on days 8-11 and 29-32 and granulocyte-macrophage colony-stimulating factor (250 mcg/m2 once daily) subcutaneously on days 8-17 and 29-38. Autologous stem cells were infused on day 15. In part B, vorinostat at 180 mg/m2 once daily was given orally on days 0-13 in combination with the part A recommended phase II dose (RP2D). Patients could receive two courses. Forty-five eligible patients enrolled, of whom 31 were evaluable. The median age was 7.5 (range, 2.9-24.1) years. For part A (n = 19), no dose-limiting toxicities (DLTs) occurred across all dose levels and courses, establishing the RP2D of MIBG to be 18 mCi/kg. In part B (n = 12), 1 DLT (grade 3 hypokalemia) occurred during course 1, and 3 of 11 patients who received a second course experienced DLT: grade 3 ALT increase, grade 4 hypoxia and grade 5 pneumonitis, and grade 3 fatigue. The best overall response rate (BORR; complete response [CR] + partial response [PR]) on part A was 42% with a CR/PR/minor response (MR) rate of 46%, and 19% progressive disease (PD) rate. For part B, the BORR was 42% with a CR/PR/MR rate of 75% and 0% PD rate. MIBG combined with dinutuximab was well tolerated with encouraging antitumor activity. Vorinostat added to this combination may augment responses in this heavily pretreated patient population.

Compressed Pineal Gland by Cavum Velum Interpositum Cyst on 68Ga-DOTATATE PET/CT

2025-06-23

Siqi Li , Keyu Zhang , Xia Lu +2 more | Clinical Nuclear Medicine

A 6-year-old boy with high-risk neuroblastoma underwent 123I-MIBG SPECT/CT, which did not reveal any abnormal 123I-MIBG accumulation. Subsequently, 68Ga-DOTATATE PET/CT demonstrated focal abnormal 68Ga-DOTATATE accumulation in the left ventricle, with … A 6-year-old boy with high-risk neuroblastoma underwent 123I-MIBG SPECT/CT, which did not reveal any abnormal 123I-MIBG accumulation. Subsequently, 68Ga-DOTATATE PET/CT demonstrated focal abnormal 68Ga-DOTATATE accumulation in the left ventricle, with no other abnormal radiotracer uptake noted elsewhere. Brain MRI revealed a cavum velum interpositum cyst compressing the pineal gland. The distribution 68Ga-DOTATATE within the compressed pineal gland on follow-up PET/CT was consistent with initial 68Ga-DOTATATE PET/CT findings. On the basis of this case, increased 68Ga-DOTATATE uptake within the compressed pineal gland represents a potential diagnostic pitfall in 68Ga-DOTATATE PET/CT imaging.

Pulmonary Toxicity Associated With Concurrent Lorlatinib and Anti‐GD2 Monoclonal Antibody Therapy in Patients With Neuroblastoma

2025-06-23

Wei Wei , Maggie Fader , Brian H. Kushner +4 more | Pediatric Blood & Cancer

The anaplastic lymphoma kinase (ALK) inhibitor lorlatinib demonstrated safety without pulmonary toxicity in early-phase trials in patients with neuroblastoma. Lorlatinib is being tested with chemotherapy and immunotherapy in the Children's … The anaplastic lymphoma kinase (ALK) inhibitor lorlatinib demonstrated safety without pulmonary toxicity in early-phase trials in patients with neuroblastoma. Lorlatinib is being tested with chemotherapy and immunotherapy in the Children's Oncology Group study ANBL1531. However, pulmonary toxicity was noted in patients receiving lorlatinib concurrently with anti-disialoganglioside 2 (GD2) monoclonal antibody (mAb) dinutuximab on the trial. After IRB approval, we performed a retrospective review on patients with neuroblastoma treated with lorlatinib and anti-GD2 mAbs from 9/2020 to 11/2024. Before 11/2023, lorlatinib was given concurrently with anti-GD2 mAbs; after 11/2023, it was withheld during mAb immunotherapy. Twenty-nine patients received lorlatinib with naxitamab (n = 12), dinutuximab (n = 11), or both (n = 6). Eight, 8, and 13 patients received lorlatinib with chemoimmunotherapy, mAbs, and both, respectively. Twenty of the 29 patients were treated with a total of 160 cycles before 11/2023, and 4 developed ≥grade 3 pulmonary toxicity. Severe respiratory failure with hemodynamic instability and the need for mechanical ventilation and extracorporeal membrane oxygenation occurred in two patients. The other two patients experienced hypoxia, wheezing, or cough, both managed with supportive care. All four recovered to <grade 3 toxicity. Three continued with lorlatinib alone or between cycles of mAbs without further >grade 2 pulmonary toxicities. Fifteen of the 29 patients were treated with 64 combined cycles after 11/2023, but none developed ≥grade 3 pulmonary toxicity. Concurrent use of lorlatinib with anti-GD2 mAbs may be associated with severe pulmonary toxicities. Temporarily withholding lorlatinib during immunotherapy appeared to mitigate this risk.

Targeted treatment for neuroblastoma using methoxyestradiol (2-ME)-loaded mitochondria-targeting immunoliposomes modified by datuximab (anti-GD2) and (L-cyclohexyl alanine-D-arginine)3 ((Fx,r)3) peptide

2025-06-23

Mingyu Wan , Zhili Chen , Yue-Yi Deng +2 more | Cancer Nanotechnology

Novel desensitization protocol utilizing conventional formulations to mitigate Temozolomide-Related skin hypersensitivity

2025-06-20

Morgan E Cantley , C. Norman Coleman , Rachael Morgan +3 more | Cancer Chemotherapy and Pharmacology

Analysis of Pro-Inflammatory and Anti-Inflammatory Cytokine Serum Concentrations in Pediatric Patients with Neuroblastoma: A Preliminary Study

2025-06-20

Silvia Selene Moreno-Guerrero , Arturo Ramírez-Pacheco , Luz María Rocha-Ramírez +4 more | Biomedicines

Background: Cytokines are effector molecules of the host immune response that have been associated with chronic inflammatory processes related to risk and a poor prognosis in cancer patients. However, the … Background: Cytokines are effector molecules of the host immune response that have been associated with chronic inflammatory processes related to risk and a poor prognosis in cancer patients. However, the impact of these molecules on the genesis and prognosis of Neuroblastoma (NB) is uncertain. Objective: The aim of the study was to analyze serum concentrations of pro-inflammatory and anti-inflammatory cytokines in a cohort of pediatric patients with NB. Methods: We evaluated the serum levels of several cytokines with a pro-inflammatory profile (IL-8, MCP-1, IL-6, IL-1β, IFN-γ, TNF-α, IL-12 p40 and IL-12p70), and anti-inflammatory profile (IL-10 and TGF-β), in pediatric patients with NB using the ELISA method, compared to a healthy control group (non-oncology). Results: Serum levels of pro-inflammatory cytokines IL-6, TNF-α, INF-γ, IL-12, IL-8 and MCP1 were significantly elevated in patients with NB compared to healthy pediatric controls. Only the anti-inflammatory cytokine IL-10 showed high levels in patients with NB in relation to the control group, unlike the synthesis of TGF-β, which had no differences between both groups. Likewise, significant positive correlations were found between the circulating levels of IL-6 with TNF-α (r = 0.667; p ≤ 0.01), IL-6 with IL-8 (r = 0.641; p ≤ 0.01), IL-8 with TNF-α (r = 0.637; p ≤ 0.01) and IL-10 with INF-γ (r = 0.542; p ≤ 0.01) in patients with NB. The simple logistic regression analysis revealed a significant association between low serum concentrations of IL-6 and a lower risk of presenting an unfavorable tumor histology (p = 0.048); in addition, low levels of IL-12p40 (p = 0.007), IFN-γ (p = 0.006) and MCP-1 (p = 0.029) were found to be associated with a lower risk of presenting NB in disseminated stages of the disease (INSS 3 and 4). Additionally, a higher risk of death was found in patients with high levels of IL-6 (p = 0.022) and IL-8 (p = 0.04). Conclusions: Taken together, the results demonstrate that the serum levels of pro-inflammatory cytokines such as IL-6, IL-8, IFN-γ, and TNF-α could be considered serum immunological indicators with a potential prognostic role in the pathogenesis of NB.

ACTG1 Inhibits PI3K/Akt Signaling Pathway to Promote Apoptosis in Gastric Cancer Cells Through Modulating Phosphatidylinositol 3-Kinase Regulatory Subunits

2025-06-20

Shi-Zhong Bian , Changquan Li | Journal of Surgery & Anesthesia Research

Gastric Cancer (GC) remains a leading cause of cancer-related mortality, with the PI3K/Akt pathway critically involved in its pathogenesis. This study identifies ACTG1 as a novel regulator of PI3K/Akt signaling, … Gastric Cancer (GC) remains a leading cause of cancer-related mortality, with the PI3K/Akt pathway critically involved in its pathogenesis. This study identifies ACTG1 as a novel regulator of PI3K/Akt signaling, demonstrating its role in inducing caspase-dependent apoptosis. Through gain- and lossof-function experiments in SGC-7901 and HGC-27 cells, we show that ACTG1 overexpression reduces p-PI3K (Tyr458) by 62% and p-Akt (Ser473) by 58%, while increasing apoptotic cell populations by 2.8-3.2-fold. Clinically, ACTG1 expression negatively correlates with p-Akt levels in GC tissues (n=80, r=-0.41, p<0.01). These findings establish ACTG1 as a potential therapeutic target for PI3K/Akt-driven gastric cancer

Closing the Gap in the Treatment of PDAC: Zenocutuzumab Could be a Potential Targeted Option for NRG1 Fusion&#x2013;Positive Disease

2025-06-19

| Default Digital Object Group

Neurofibromatosis type 1 with relapsed/refractory precursor B-lymphoblastic lymphoma: Case report and literature review

2025-06-19

Hongjuan Li , Yanli Leng , Yan Gu +4 more | Case Reports in Oncology

Introduction: Concomitant occurrence of B-lymphoblastic lymphoma (B-LBL) and neurofibromatosis type 1 (NF1) is rare. Case presentation: We diagnosed and treated a child presenting with NF1 and relapsed B-LBL and reviewed … Introduction: Concomitant occurrence of B-lymphoblastic lymphoma (B-LBL) and neurofibromatosis type 1 (NF1) is rare. Case presentation: We diagnosed and treated a child presenting with NF1 and relapsed B-LBL and reviewed the relevant literature through the last 8 years. Stage IV precursor B-LBL with central nervous system 3 was identified in this patient, with pain and activity abnormalities in both lower limbs. NF1 was diagnosed based on physical examination, brain magnetic resonance imaging, genetic testing, and family history. The patient relapsed after chemotherapy and was given blinatumomab. After one week of blinatumomab treatment, the lower limb pain was relieved. The child underwent umbilical cord blood transplantation after completing two sessions of blinatumomab therapy and is still disease-free to date. Conclusion: The findings from this study will offer valuable empirical references for peers treating NF1 associated with refractory/relapsed B-LBL.

Development of intelligent tools to predict neuroblastoma risk stratification and overall prognosis based on multiphase enhanced CT and clinical features

2025-06-19

Wei Zhao , Yahui Han , Xiaokun Yu +3 more | Frontiers in Neurology

Background Neuroblastoma (NB) is a common malignancy in children, and accurate risk stratification and prognostic assessment are essential for personalized treatment. Current tumor assessment methods rely on clinical features and … Background Neuroblastoma (NB) is a common malignancy in children, and accurate risk stratification and prognostic assessment are essential for personalized treatment. Current tumor assessment methods rely on clinical features and conventional imaging techniques, which have limited predictive accuracy. The aim of this study was to develop a deep learning model based on multiphase enhanced CT images and clinical features to improve the accuracy of risk stratification and prognostic assessment of NB. Methods Multi-phase enhanced CT images and clinical features from 202 NB patients were collected. Four risk stratification classifiers were developed using the Swin Transformer model and evaluated in training and testing cohorts. Prognostic models were constructed using a combination of multiple machine learning algorithms in conjunction with CT image features and clinical characteristics. Results Swin-ART based on arterial phase images was the best risk stratification classifier with an AUC of 0.770 (95% CI: 0.613–0.909) and an accuracy of 0.780 in the testing cohort. In the prognostic assessment, the combined model of backward stepwise Cox regression and randomized survival forest (RSF) obtained the highest mean C-index of 0.84. The 1-, 3-, and 5-year AUC values of the optimal prognostic model in the training cohort were 0.93 (95% CI: 0.927–0.942), 0.93 (95% CI: 0.929–0.946), and 0.96 (95% CI: 0.953–0.974), respectively. The corresponding AUC values for the testing cohort were 0.90 (95% CI: 0.857–0.934), 0.87 (95% CI: 0.808–0.928), and 0.91 (95% CI: 0.718–0.977), respectively. Multimodal models outperform single-modality clinical models in both predictive accuracy and stability. Conclusion This study successfully developed a deep learning model based on multiphase enhanced CT images and clinical features to predict risk stratification and prognosis in NB. The findings provide a new tool for clinical practice and lay the foundation for future precision medicine and personalized treatment.

Amniotic membrane promotes doxorubicin potency by suppressing SH-SY5Y neuroblastoma cell angiogenesis

2025-06-19

Ahmed M. Abou‐Shanab , Shaimaa Shouman , Alaa E. Hussein +6 more | BMC Cancer

Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment

2025-06-18

Judit Liaño-Pons , Elisa Garde-Lapido , Fenja L. Fahrig +7 more | Proceedings of the National Academy of Sciences

Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of the MYCN oncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming … Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of the MYCN oncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, both PRDX6 and GSTP1 are highly expressed in the developing murine adrenal gland, as well as in high-risk, MYCN -amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.

High-risk neuroblastoma in Mexico: from multimodal treatment to immunotherapy. Regarding the first case treated with naxitamab

2025-06-18

Alberto Olaya‐Vargas , Haydeé Salazar-Rosales , Marcela Concepción Caballero‐Palacios +7 more | Frontiers in Oncology

Introduction We report herein the case of a patient diagnosed with high-risk neuroblastoma (HR-NB), treated with naxitamab following suboptimal response to induction chemotherapy, becoming the first patient to receive this … Introduction We report herein the case of a patient diagnosed with high-risk neuroblastoma (HR-NB), treated with naxitamab following suboptimal response to induction chemotherapy, becoming the first patient to receive this therapy at the National Institute of Pediatrics (INP) in Mexico. We discuss the clinical course, therapeutic approach, response to treatment, adverse events, and fatal outcome, focusing on the implications of immunotherapy access in low- and middle-income countries (LMIC). Case presentation A 2-year-old male presented with a 3-month history of a left front-temporal mass and left-sided exophthalmos. Magnetic resonance imaging (MRI) revealed a poorly defined retroperitoneal and paravertebral mass, and a destructive cranial lesion involving the sphenoid wing and the orbit. PET-CT and MIBG scans confirmed widespread metastatic disease in bone, orbit, and intracranial structures, consistent with stage 4 neuroblastoma. Histopathology of a cranial biopsy confirmed poorly differentiated neuroblastoma. The patient was classified as high-risk based on age and metastatic disease, and underwent multimodal treatment including chemotherapy, partial tumor resection, radiotherapy, and anti-GD2 immunotherapy with naxitamab under protocol HITS-17-251. After five cycles, imaging showed complete response in cranial metastases. Adverse events during immunotherapy were mild (Grade I–II), including erythema, pruritus, urticaria, and transient hypotension, all managed with antihistamines and IV fluids. However, one month after the final cycle, the patient developed sudden neurological deterioration with cerebral edema and hydrocephalus. Despite intensive care, he progressed to brain death, with neurotoxicity suspected as the cause. Discussion The primary objective of implementing novel immunotherapeutic strategies, in addition to improving event-free survival (EFS) and overall survival (OS) in patients diagnosed with high-risk neuroblastoma, is to reduce adverse effects and lower both short- and long-term mortality. It is worth noting that the current cost of anti-GD2 therapies available in Latin America is estimated to exceed $450,000 USD. In a country like Mexico, where the minimum daily wage is approximately $10 USD, access to these therapies remains unattainable for the majority of the population. Therefore, it is essential to highlight the importance and substantial clinical impact of immunotherapy on survival outcomes in patients with refractory neuroblastoma. This recognition should support advocacy for broader access to these therapies. Despite their high costs, the demonstrated benefits should outweigh the disadvantages, justifying efforts to make them accessible to all patient populations. Conclusions Future studies in LMICs including Mexico and Latin America, must focus on optimizing dosing strategies to minimize adverse effects and improve both survival outcomes and the quality of life for patients receiving immunotherapy.

A novel therapeutic strategy for osteosarcoma using anti-GD2 ADC and EZH2 inhibitor

2025-06-18

Jing Shan , Zoe Lin , Harunor Rashid +7 more | Biomarker Research

Quantitative Proteomics Unveils the Synergistic Effects of Combination Drugs on Cytoskeleton Composition and Autophagy-Mediated Cell Death in Neuroblastoma

2025-06-17

Peichen Yu , Yi-Chun Kao , Hsin‐Yi Chang +4 more | Journal of Proteome Research

Neuroblastoma, a prevalent and aggressive childhood cancer, lacks effective treatments. Recent research highlights the repurposing of existing drugs as a strategy for breakthroughs in combating this disease. We systematically analyzed … Neuroblastoma, a prevalent and aggressive childhood cancer, lacks effective treatments. Recent research highlights the repurposing of existing drugs as a strategy for breakthroughs in combating this disease. We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), identifying pyrvinium pamoate and sirolimus, two FDA-approved drugs, as potential candidates for neuroblastoma combination therapy. Colony formation assays and organoid culture confirmed that the therapeutic effect of combining these two drugs exceeded that of either drug alone. The mRNA expression levels of several genes predicted by LINCS also decreased. To comprehensively understand the mechanism behind superior efficacy of the combination therapy compared to monotherapy, we performed quantitative proteomics with tandem mass tag labeling and identified 3416 proteins from 20,623 peptides. Gene set enrichment analysis and Database for Annotation, Visualization, and Integrated Discovery revealed that combination therapy significantly decreased cytoskeleton formation compared with monotherapy, reflecting dramatic reduction in cell migration. Additionally, the research indicated that cell cycle arrest occurred under combination therapy. Furthermore, we confirmed that the extent of autophagy significantly increased after the combination treatment. In summary, this study elucidates the mechanisms and therapeutic potential of combining sirolimus and pyrvinium pamoate for treating neuroblastoma, offering new advancements for this challenging disease.

Feasibility of Single Time Point Dosimetry Application in 177Lu-DOTATATE/DOTATOC-treated Pediatric Neuroblastoma

2025-06-17

Xingyao Sun , Fei Zheng , Yuxuan Liu +5 more | Clinical Nuclear Medicine

Background: 177 Lu-DOTATATE/DOTATOC peptide receptor radionuclide therapy (PRRT) has demonstrated potential for treating pediatric neuroblastoma (NB), and in clinical practice can be measured dosimetry by multi–time point (MTP) dosimetry. However, … Background: 177 Lu-DOTATATE/DOTATOC peptide receptor radionuclide therapy (PRRT) has demonstrated potential for treating pediatric neuroblastoma (NB), and in clinical practice can be measured dosimetry by multi–time point (MTP) dosimetry. However, the high workload and limited patient compliance associated with MTP restrict its application. Consequently, single time point (STP) dosimetry approaches have emerged as a promising alternative, though their effectiveness in pediatric populations has not been thoroughly investigated. This study aimed to assess the dosimetric determination of 177 Lu-DOTATATE/DOTATOC in pediatric neuroblastoma patients to determine whether STP could serve as a viable replacement for MTP. Patients and Methods: A total of 24 pediatric NB patients who received 1 to 2 cycles of 177 Lu-DOTATATE or 177 Lu-DOTATOC underwent dosimetric measurement of lesions and critical organs using the 96 hours single time point (STP H ) dosimetry method proposed by Hänscheid and colleagues. The results were compared with those obtained from standard MTP. Results: In patients treated with 177 Lu-DOTATATE, the mean relative deviation absolute values of the STP H -calculated absorbed dose from MTP were <10% for lesions, kidneys, bone marrow, liver, and spleen, with Pearson correlation coefficients of 0.99, 0.93, 0.97, 0.84, and 0.84, respectively. In patients treated with 177 Lu-DOTATOC, the mean relative deviation absolute values for kidneys, spleen, and bone marrow were <10%, with Pearson correlation coefficients of 0.97, 0.77, 0.35, 0.48, and 0.93 for lesions, kidneys, bone marrow, liver, and spleen, respectively. Conclusions: The findings confirm that the 96 hours STP H method can reliably replace MTP for dosimetric assessment in pediatric NB patients treated with 177 Lu-DOTATATE and performed well in renal dosimetry for 177 Lu-DOTATOC therapy.

Precision prognostication in neuroblastomas via clinically validated E2F activity signatures

2025-06-17

De Cai , Huihuang Xu , Shiwei He +2 more | Frontiers in Immunology

Background Neuroblastoma (NB) is the most common extracranial solid tumor in children, with high-risk NB (HR-NB) exhibiting dismal survival rates due to aggressive biology and therapy resistance. E2F transcription factors … Background Neuroblastoma (NB) is the most common extracranial solid tumor in children, with high-risk NB (HR-NB) exhibiting dismal survival rates due to aggressive biology and therapy resistance. E2F transcription factors (E2Fs) are pivotal regulators of cell cycle progression and immune modulation, yet their prognostic and therapeutic implications in NB remain underexplored. Methods Using transcriptomic data from the GEO, TARGET, and E-MTAB-8248 cohorts, we identified E2F-associated molecular subtypes via consensus clustering. A prognostic signature was constructed via LASSO regression and validated for risk stratification. Immune infiltration, tumor mutation burden (TMB), and drug sensitivity were analyzed via the CIBERSORT, ESTIMATE, and GDSC databases. Results Four E2F-related genes (MAD2L1, CDC25A, CKS2, and NME1) were used to construct a prognostic nomogram that stratified patients into high- and low-risk groups, with low-risk patients exhibiting superior overall survival (P &lt; 0.05). Multivariate Cox regression confirmed that the model was an independent prognostic factor (P &lt; 0.001). High-risk patients presented lower immune and stromal scores, reduced immune checkpoint expression, distinct immune cell infiltration patterns, and significant differences in mutation spectrum and drug sensitivity (P &lt; 0.001). Conclusions The E2F-related prognostic signature effectively stratifies NB patients by risk and provides potential biomarkers for prognosis and targeted therapy in HR-NB patients. The identified signature enhances patient stratification and provides insights into NB tumor biology, the immune landscape, and potential treatment strategies.

The Non‐Coding Regulatory Variant rs2863002 at chr11p11.2 Increases Neuroblastoma Risk by Affecting HSD17B12 Expression and Lipid Metabolism

2025-06-17

Teresa Maiorino , Marianna Avitabile , Vincenzo Aievola +7 more | Advanced Science

Abstract A Genome‐wide association study (GWAS) on a European‐American cohort identified chr11p11.2 as a neuroblastoma predisposition locus. Combining in‐house and public genomic data from neuroblastoma cell lines, this work implicates … Abstract A Genome‐wide association study (GWAS) on a European‐American cohort identified chr11p11.2 as a neuroblastoma predisposition locus. Combining in‐house and public genomic data from neuroblastoma cell lines, this work implicates rs2863002 as the candidate causal variant at the 11p11.2 locus, confirming its cis‐regulatory activity through a luciferase reporter assay. The genetic association of rs2863002 with neuroblastoma risk is validated in an Italian case‐control cohort. Using ChIP‐qPCR, Hi‐C, and CRISPR genome editing, this work deciphers the regulatory mechanisms at the risk locus, demonstrating that the rs2863002‐C risk allele regulates HSD17B12 expression and reduces GATA3 binding affinity. In vitro functional assays and targeted lipidomic analyses reveal the involvement of the rs2863002‐C risk allele in tumorigenicity and modulation of lipid metabolism in neuroblastoma cells through HSD17B12 regulation. This study provides new insights into the genetic basis of neuroblastoma and underscores the importance of post‐GWAS functional characterization of risk loci in uncovering relevant biological findings for understanding complex diseases.

Mechanistic insights into transcriptional regulation of ARHGAP36 expression identify a factor predictive of neuroblastoma survival

2025-06-16

Serhiy Havrylov , Armin M. Gamper , Ordan J. Lehmann | bioRxiv (Cold Spring Harbor Laboratory)

Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage specific transcription factors that regulate neural crest migration representing frequent drivers of malignancy. … Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage specific transcription factors that regulate neural crest migration representing frequent drivers of malignancy. One such example is the forkhead transcription factor FOXC1 where gain of function is a feature of diverse cancers that is associated with an unfavourable prognosis. Using RNA-, ChIP-sequencing and CRISPR interference, we show that Foxc1 binds a locus in a region of closed chromatin to induce expression of Arhgap36, a tissue-specific inhibitor of Protein Kinase A. Because PKA is a core Hedgehog (Hh) pathway inhibitor, Foxc1's induction of Arhgap36 expression increases Hh activity. The function of Sufu, a PKA substrate and a second essential Hh pathway inhibitor, is likewise impaired. The resulting increased Hh pathway output is resistant to pharmacological inhibition of Smoothened , a phenotype of more aggressive cancers. The Foxc1-Arhgap36 relationship identified in murine cells was further evaluated in neuroblastoma, a neural crest derived pediatric malignancy. This demonstrated in a cohort of 1348 patients that high levels of ARHGAP36 are predictive of improved five-year survival. In individual neuroblastoma cell lines that express high levels of ARHGAP36, the acute suppression of ARHGAP36 by shRNA inhibition induced apoptosis and rapid cell death. Accordingly, this study has identified as a novel transcription factor which enhances ARHGAP36 expression, one that induces Hh activity in multiple tissues during development. It also establishes a model by which increased levels of FOXC1 via ARHGAP36 and PKA inhibition, dysregulate multiple facets of Hh signaling, and provides evidence demonstrating relevance to a common neural-crest derived malignancy.

Long-Term Outcomes Of Patients With Stage IV Neuroblastoma(NB) In Bangladesh Shishu Hospital

2025-06-14

| Journal of Community Medicine and Public Health Reports

Paediatric Tumors

2025-06-14

| TNM Online

Abstract Describing cancer stage is one of the most important elements of oncological practice. Clinical research and clinical care depend on an accurate assessment of cancer stage and prognostic factors. … Abstract Describing cancer stage is one of the most important elements of oncological practice. Clinical research and clinical care depend on an accurate assessment of cancer stage and prognostic factors. The consensus meetings held in 2014 and 2019 recommended a tiered staging system with more‐detailed systems for well‐resourced cancer registries and less‐detailed systems for registries with limited resources and access; as with Essential TNM, lower‐tiered systems are based on collapsing higher‐tiered systems. For some cancers, recommendations are the same as described earlier for adult patients and the appropriate page number is given; others are referenced where appropriate. Rules for the derivation of paediatric cancer stage in population‐based cancer registries are available from the UICC website. The classification applies only to paediatric malignant tumours. The prognostic grouping for rhabdomyosarcoma includes favourable anatomical sites and unfavourable anatomical sites.

[68Ga]Ga-DOTA-TOC positron emission tomography outperforms [18F]FDOPA and [18F]FDG PET in pediatric neuroblastoma imaging: a prospective study

2025-06-13

Chia‐Ju Liu , Kuan‐Yin Ko , Meng‐Yao Lu +7 more | European Journal of Nuclear Medicine and Molecular Imaging

2-OR: Blocking Neuroblastoma Suppressor of Tumorigenicity 1 (NBL1) Prevents Diabetic Kidney Disease

2025-06-13

Adriana Petrazzuolo , Emma Assi , Anna Maestroni +7 more | Diabetes

Introduction and Objective: Serum levels of neuroblastoma suppressor of tumorigenicity 1 (NBL1) positively correlate with the 10-years risk of developing end stage kidney disease (ESKD) in patients with either type … Introduction and Objective: Serum levels of neuroblastoma suppressor of tumorigenicity 1 (NBL1) positively correlate with the 10-years risk of developing end stage kidney disease (ESKD) in patients with either type 1 or type 2 diabetes. Moreover, NBL1 causes podocyte death, in vitro. The aim of our study was to test whether NBL1 blocking agents could prevent podocyte death, in vitro, and delay diabetic kidney disease (DKD) onset, in vivo. Methods: We screened a library of NBL1 inhibitors through phage display by using an in vitro cell death assay, which measured NBL1-induced apoptosis of human immortalized podocytes. Stem cell-derived human kidney organoids were used as translational model. NBL1 inhibitors were tested, in vivo, in streptozotocin (STZ)-induced DKD and in Db/Db mice. Efficacy of NBL1 blocking agents was evaluated by quantifying mesangial expansion, pro-fibrotic response, expression of podocyte-specific markers and by measuring urinary creatinine and albumin. Results: Our study demonstrated that NBL1 inhibition markedly reduced NBL1-induced podocyte death, in vitro, and rescued the expression of podocyte markers in human kidney organoids. More importantly, when administered in vivo, NBL1 inhibitors reduced urinary albumin and creatinine, mesangial expansion, and renal fibrosis, thus preventing the development of DKD. Conclusion: Novel therapies aimed at blocking/delaying DKD onset and/or progression to ESKD in patients with diabetes are still needed. Our findings demonstrate that NBL1 inhibition protects diabetic mice from renal damage by preventing podocyte death, thereby confirming NBL1 as novel therapeutic target for DKD. Disclosure A. Petrazzuolo: None. E. Assi: None. A. Maestroni: None. V. Usuelli: None. M. Zocchi: None. G. Rossi: None. I. Pastore: Advisory Panel; Sanofi. Board Member; Novo Nordisk. A. Monestiroli: Consultant; Nephris, Alia Therapeutics. M. Ben Nasr: None. F. D'Addio: Advisory Panel; Sanofi. A. Krolewski: None. P. Fiorina: Consultant; Novo Nordisk, AstraZeneca. Board Member; Boehringer-Ingelheim.

1336-P: Exploring the Spectrum of HNF1A-MODY in Three Pediatric Patients—From Diagnosis to Management

2025-06-13

SYDNEY LOOK , REEM SHAWAR | Diabetes

Introduction and Objective: Monogenic diabetes (also known as maturity-onset diabetes of the young [MODY]) is a group of inherited non-autoimmune diabetes which typically presents in adolescence or young adulthood. Hepatocyte … Introduction and Objective: Monogenic diabetes (also known as maturity-onset diabetes of the young [MODY]) is a group of inherited non-autoimmune diabetes which typically presents in adolescence or young adulthood. Hepatocyte nuclear factor 1 homeobox A (HNF1A) variants are associated with autosomal dominant monogenic diabetes known as HNF1A-MODY. This case series aims to describe the variability in presentation and management in 3 patients with confirmed or likely HNF1A-MODY. Methods: We describe the clinical characteristics, diagnostic evaluation, and treatment approaches of 3 pediatric patients with confirmed or likely HNF1A-MODY at Primary Children’s Hospital. Results: Table 1 summarizes the clinical characteristics, biochemical and genetic evaluation, and management. Conclusion: In conclusion, this case series highlights the importance of appropriately identifying youth with HNF1A-MODY despite its clinical heterogeneity on presentation. Pharmacotherapy should be individualized to achieve adequate glycemic control in this unique patient population. Disclosure S. Look: None. R. Shawar: None.

CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity

2025-06-12

Marcelo M. Rodríguez , Debashree Chatterjee , Johanna Guerry +7 more | Proceedings of the National Academy of Sciences

Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a … Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a vertebrate-specific orphan enzyme, as an unprecedented eukaryotic dCTP deaminase. CDADC1 catalyzes the conversion of dCTP into dUTP. While bacteria use this activity to sustain proliferation, CDADC1 evolved independently and is not required for mammalian cell proliferation, as demonstrated in cell lines and by the normal growth and standard lifespan of Cdadc1-deficient mice. However, we uncover a role of CDADC1 in metabolizing nucleotide analogs gemcitabine and decitabine. Gain- and loss-of-function assays in cancer cell lines, along with ectopic mouse models of pancreatic cancer, show that CDADC1 reduces these drugs’ efficacy. By the same token, Cdadc1 −/− mice are hypersensitive to gemcitabine. Mechanistically, CDADC1 deaminates the active triphosphate form of gemcitabine and decitabine, rendering them susceptible to inactivation by deoxyuridine triphosphatase. In contrast, the dCMP deaminase DCTD contributes to cell proliferation and promotes gemcitabine and decitabine toxicity. Thus, CDADC1 underpins a previously unrecognized mechanism of intrinsic chemoresistance in cancer cells and has a nonredundant role in protecting from gemcitabine toxicity. CDADC1 reveals a clinically relevant metabolic pathway that might be exploited to enhance the efficacy of deoxycytidine analogs but calls for assessing CDADC1 status to avoid lethal toxicities.

Accelerating Drug Development for Neuroblastoma: Consensus Statement From the Third Neuroblastoma Drug Development Strategy Forum

2025-06-12

Steven G. DuBois , Lucas Moreno , John Anderson +7 more | Pediatric Blood & Cancer

ABSTRACT High‐risk neuroblastoma is a poor prognosis cancer of the sympathetic nervous system that accounts for a disproportionate number of childhood cancer deaths. Many viable biological targets have been identified, … ABSTRACT High‐risk neuroblastoma is a poor prognosis cancer of the sympathetic nervous system that accounts for a disproportionate number of childhood cancer deaths. Many viable biological targets have been identified, and the number of potential combinations is even larger. Several products have attained marketing authorization for treatment of patients with neuroblastoma. Patient outcomes remain poor, with approximately 50% of children with newly diagnosed high‐risk neuroblastoma cured of their disease. International, multistakeholder Neuroblastoma Drug Development Strategy (NDDS) meetings were established more than a decade ago. This third NDDS meeting included academia, industry, regulatory, and patient advocacy representatives to prioritize agents and to address key challenges in drug development in this disease. Given the central role that anti‐GD2 therapy plays, novel GD2‐directed combinations were a key focus, including epigenetic enzymes such as EZH2 and immunologic targets such as IL15 and TIGIT as potential combination partners. GD2‐directed chimeric antigen receptor (CAR)‐T cells were a top priority, along with emerging CAR‐T targets such as B7‐H3 and GPC2. Recognizing that combination therapies are likely to be most impactful for patients and for advancing therapies to frontline, another key focus was on high priority combinations of targeted therapies, including Aurora A kinase plus BCL2 or ATR inhibitors. Additional targets and agents were prioritized or deprioritized based upon current data. Access to drugs for clinical trials was viewed as a major barrier to progress. Strategies to overcome this challenge focused on united efforts by the international scientific and advocacy community and early engagement by industry with regulatory authorities.

DBSCAN and DBCV application to open medical records heterogeneous data for identifying clinically significant clusters of patients with neuroblastoma

2025-06-12

Davide Chicco , Luca Oneto , Davide Cangelosi | BioData Mining

[Progress on the genetic mechanisms and research models of neuroblastoma in children].

2025-06-08

Yanwei Bi , Yaqing Liu | PubMed

CellCorticalDisplastic: simulador educativo de la recuperación de la desensibilización del receptor N-metil-D-aspartato

2025-06-04

Marleni Reyes Monreal , María Eugenia Pérez Bonilla , Jessica Quintero Pérez +2 more | Acta Universitaria

El receptor N-metil-D-aspartato (NMDA) constituye un componente importante de las sinapsis excitatorias. No existen simuladores educativos que aborden la recuperación de la desensibilización del receptor NMDA. En este contexto, se … El receptor N-metil-D-aspartato (NMDA) constituye un componente importante de las sinapsis excitatorias. No existen simuladores educativos que aborden la recuperación de la desensibilización del receptor NMDA. En este contexto, se ha concebido un simulador educativo orientado a la enseñanza de este proceso. Para interesar a los alumnos, se basó en registros electrofisiológicos de la recuperación de la desensibilización en tres tipos de células de la corteza de un paciente pediátrico con displasia cortical: neuronas localizadas fuera de la corteza displásica (NO-CD), neuronas de la corteza displásica aparentemente normales (CD-aparentemente normales) y neuronas citomegálicas de la corteza displásica (CD-citomegálicas). El simulador reproduce la recuperación de la desensibilización de cada una de estas células, validando los procesos modelados. El modelo matemático implementado permitió estimar teóricamente la concentración de calcio interno en los experimentos reportados. El simulador cuenta con un conjunto de lecciones que introduce al alumno en el tema y permite realizar prácticas virtuales.

Semi-quantitative MIBG Scores in Relapsed/Refractory Neuroblastoma: Prognostic Insights from Post-131I-MIBG Treatment Scans and Impact of SPECT-CT Imaging

2025-06-01

Mehmet Emin Mavi , Pınar Özgen-Kıratlı , Ali Varan +1 more | Revista Española de Medicina Nuclear e Imagen Molecular (English Edition)