scholarly journals Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Children ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 482
Author(s):  
Irene Paraboschi ◽  
Laura Privitera ◽  
Gabriela Kramer-Marek ◽  
John Anderson ◽  
Stefano Giuliani
Keyword(s):  
Research Effort ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Treatment Protocols ◽  
Ongoing Research ◽  
Hematopoietic Stem ◽  
Novel Treatments ◽  
Therapeutic Modalities ◽  
High Risk Disease ◽  
Novel Treatment Strategies

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40–50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB’s cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

scholarly journals Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

2019 ◽  
Vol 68 (1) ◽  
pp. 33-57 ◽  
Author(s):  
Vashendriya V.V. Hira ◽  
Barbara Breznik ◽  
Miloš Vittori ◽  
Annique Loncq de Jong ◽  
Jernej Mlakar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Primary Brain Tumor ◽  
Hematopoietic Stem ◽  
Glioblastoma Recurrence ◽  
Novel Treatment Strategies ◽  
Differentiation And Proliferation ◽  
Immunohistochemical Analyses

Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.

scholarly journals ROLE OF HEMATOPOIETIC STEM CELL TRANSPLANTATION

2012 ◽  
Vol 4 (1) ◽  
pp. e2012059 ◽  
Author(s):  
Angelo Michele Carella
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Brentuximab Vedotin ◽  
New Drugs ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Novel Treatment Strategies

Hodgkin lymphoma is one of the most curable human tumors. Despite this, about 30% of these patients relapsed or are primary refractory to the first line treatment. Autografting is generally considered the standard of care for these patients. Alternative salvage strategies have been evaluated such as high dose sequential and tandem autografting strategies. In younger patients,  refractory or early relapsed after autografting, allogeneic stem cell transplantation has been employed but this approach has been followed by significant concerns since the treatment related mortality often exceeded 40-50%, and relapses were not uncommon. It is clear that patient selection remains an issue in all allografting reports.At the end, new drugs and novel treatment strategies, that are based on our understanding of the disease biology and signaling pathways, are needed to improve treatment outcome for these patients. The two leading compounds Brentuximab Vedotin and Panobinostat, are currently under evaluation  in several clinical trials.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

scholarly journals Inhibition of ITK differentiates GVT and GVHD in allo-HSCT

2020 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Cytokines ◽  
Treatment Strategies ◽  
Peptide Inhibitor ◽  
List Type ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Novel Treatment Strategies ◽  
And Migration

AbstractAllogeneic hematopoietic stem cell transplantation is a life-saving treatment for many malignant and nonmalignant diseases. Donor T cells contained within the graft prevent tumor recurrence via graft-versus-tumor (GVT) effects, however, also cause graft-versus-host disease (GVHD). Novel treatment strategies are therefore needed to allow maintenance of GVT while suppressing GVHD. Here we show using murine models, that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving the beneficial GVT effects. Donor T cells from Itk-/- mice exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs such as liver and small intestine, while maintaining GVT efficacy against primary B-ALL tumors. Itk-/- T cells exhibited reduced expression of IRF4 and decreased JAK/STAT signaling activity, but preserved cytotoxicity, which was accompanied by upregulation of Eomesodermin (Eomes), which was necessary for GVT function. A novel peptide inhibitor ITK signaling is also able to prevent GVHD. This novel peptide inhibitor also reduced cytokine production in mice and human T cells. Altogether, our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVT effects following allo-HSCT treatment.Key PointsInhibiting ITK by a novel peptide significantly reduces GVHD but retains GVT.ITK deficient donor T cells exhibit minimal GVHD, but maintain GVT activity.ITK deficient donor T cells exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs.Eomes is required for GVT effect.

scholarly journals Management of critical-sized bone defects in the treatment of fracture-related infection: a systematic review and pooled analysis

2020 ◽  
Author(s):  
H. Bezstarosti ◽  
W. J. Metsemakers ◽  
E. M. M. van Lieshout ◽  
L. W. Voskamp ◽  
K. Kortram ◽  
...  
Keyword(s):  
Systematic Review ◽  
Treatment Strategies ◽  
Bone Defects ◽  
Bone Transport ◽  
Adverse Outcomes ◽  
Classification Systems ◽  
Success Rates ◽  
Local Antibiotics ◽  
Treatment Protocols ◽  
Membrane Technique

Abstract Purpose This systematic review determined the reported treatment strategies, their individual success rates, and other outcome parameters in the management of critical-sized bone defects in fracture-related infection (FRI) patients between 1990 and 2018. Methods A systematic literature search on treatment and outcome of critical-sized bone defects in FRI was performed. Treatment strategies identified were, autologous cancellous grafts, autologous cancellous grafts combined with local antibiotics, the induced membrane technique, vascularized grafts, Ilizarov bone transport, and bone transport combined with local antibiotics. Outcomes were bone healing and infection eradication after primary surgical protocol and recurrence of FRI and amputations at the end of study period. Results Fifty studies were included, describing 1530 patients, the tibia was affected in 82%. Mean age was 40 years (range 6–80), with predominantly male subjects (79%). Mean duration of infection was 17 months (range 1–624) and mean follow-up 51 months (range 6–126). After initial protocolized treatment, FRI was cured in 83% (95% CI 79–87) of all cases, increasing to 94% (95% CI 92–96) at the end of each individual study. Recurrence of infection was seen in 8% (95% CI 6–11) and amputation in 3% (95% CI 2–3). Final outcomes overlapped across treatment strategies. Conclusion Results should be interpreted with caution due to the retrospective and observational design of most studies, the lack of clear classification systems, incomplete data reports, potential underreporting of adverse outcomes, and heterogeneity in patient series. A consensus on classification, treatment protocols, and outcome is needed to improve reliability of future studies.

scholarly journals Novel Therapies for Relapsed and Refractory Neuroblastoma

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 148 ◽  
Author(s):  
Peter Zage
Keyword(s):  
Clinical Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disease Relapse ◽  
Therapeutic Modalities ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Improved Outcomes ◽  
Outcomes For Children ◽  
Novel Treatment Strategies

While recent increases in our understanding of the biology of neuroblastoma have allowed for more precise risk stratification and improved outcomes for many patients, children with high-risk neuroblastoma continue to suffer from frequent disease relapse, and despite recent advances in our understanding of neuroblastoma pathogenesis, the outcomes for children with relapsed neuroblastoma remain poor. These children with relapsed neuroblastoma, therefore, continue to need novel treatment strategies based on a better understanding of neuroblastoma biology to improve outcomes. The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma, and additional clinical trials using molecular and genetic tumor profiling to target tumor-specific aberrations are ongoing. Combinations of these new therapeutic modalities with current treatment regimens will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma.

scholarly journals Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Angelica Trujillo ◽  
Christie McGee ◽  
Christopher R. Cogle
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Autocrine Stimulation ◽  
Novel Treatment Strategies ◽  
Relapsed Disease ◽  
Acute Myeloid

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed.

scholarly journals Monitoring Immune Responses in Neuroblastoma Patients during Therapy

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 519 ◽  
Author(s):  
Celina L. Szanto ◽  
Annelisa M. Cornel ◽  
Saskia V. Vijver ◽  
Stefan Nierkens
Keyword(s):  
High Risk ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Current Treatment ◽  
Immune Monitoring ◽  
Treatment Protocols ◽  
High Risk Disease ◽  
New Treatment ◽  
Tumor In Childhood ◽  
Monitoring Protocols

Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.

Recurrent and reversible bilateral palmar blue discoloration following administration of liposomal daunorubicin-cytarabine (Vyxeos®) for acute myeloid leukemia with myelodysplasia-related changes

2020 ◽  
pp. 107815522097845
Author(s):  
Katherine Triesel ◽  
Timothy Chiang ◽  
Robert Seabury ◽  
Christopher Miller
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Treatment Strategies ◽  
Liposomal Daunorubicin ◽  
Therapeutic Modalities ◽  
First Case ◽  
Blue Discoloration ◽  
Novel Treatment Strategies ◽  
Acute Myeloid

Introduction With novel treatment strategies for acute myeloid leukemia becoming more readily utilized in the clinical practice setting, new data on potential treatment-related adverse events also has become available. Case report We present a patient case on a previously unreported potential adverse event related to liposomal daunorubicin-cytarabine administration. The patient experienced bilateral discoloration of the palms of his hands that resolved after completion of the treatment cycle, only to recur at cycle two of therapy. Management and outcome: No intervention was required as the condition resolved within a week of onset. Discussion With newer therapeutic modalities becoming more used in the clinical setting, it is important to understand the potential risks of treatment-related adverse events that come with them. To our knowledge this is the first case reporting blue-skin discoloration related to liposomal daunorubicin-cytarabine.

scholarly journals Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

2018 ◽  
Author(s):  
Courtney R. Sullivan ◽  
Catharine A. Mielnik ◽  
Sinead M. O’Donovan ◽  
Adam J. Funk ◽  
Eduard Bentea ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Treatment Strategies ◽  
Long Term Memory ◽  
Peroxisome Proliferator ◽  
Integrated Network ◽  
Peroxisome Proliferator Activated Receptor ◽  
Novel Treatments ◽  
Ppar Agonists ◽  
Novel Strategy ◽  
Novel Treatment Strategies

ABSTRACTWe utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n=16) and control (n=16) subjects and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of “reversing” the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens may be employed to identify novel treatment strategies for schizophrenia and related diseases.

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