1. Recent Articles

    1. Patterns of Diagnosis and Misdiagnosis in Pediatric Cancer and Relationship to Survival.

      "The median time from symptom onset to diagnosis was shortest for leukemia (18.5 d) and longest for bone tumors (86.5 d). Tumor type was the only factor associated with time to diagnosis. In 52% of cases an incorrect nononcological diagnosis was initially made. Soft tissue sarcomas and brain tumors were misdiagnosed most often. Neither prolonged time to diagnosis nor initial misdiagnosis was associated with reduced survival. Tumor type and presence of metastatic disease at diagnosis were significantly associated with survival."

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    2. Implantable Chemotherapy-Loaded Silk Protein Materials for Neuroblastoma Treatment.

      "Furthermore, intra-tumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor ...

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    3. Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients.

      "Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5-hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly ...

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      Mentions: Genetics
    4. The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs.

      "Treatment with JQ1 blocked the recruitment of Nrf2 to the antioxidant responsive elements at Nrf2 target gene promoters, and JQ1 exerted synergistic anticancer effects with nanaomycin by blocking the Nrf2-antioxidant signaling pathway. JQ1 and vincristine synergistically induced neuroblastoma cell cycle arrest at the G2/M phase, aberrant mitotic spindle assembly formation and apoptosis, but showed no effect on cell survival in normal non-malignant cells. Importantly, co-treatment with JQ1 and vincristine synergistically suppressed tumor progression in neuroblastoma-bearing mice. These results strongly suggest that patients treated with BET bromodomain inhibitors in clinical trials should be co-treated with vincristine."

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      Mentions: Treatment
    5. TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells.

      "Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors, TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against NB cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth ...

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    6. Parents of children with cancer value sequencing results, even if non-actionable

      "There is a general, ethical inclination to be reluctant to disclose sequencing information without clear clinical utility, especially when children are involved," said Dr. Malek, who presented the research. "However, our study showed that parents find this information useful in a much broader way than clinicians might expect," she said.  For example, many parents cited psychological benefits to receiving the information. "Almost all of the parents we interviewed wanted to know where the cancer had come from," Dr. Malek explained. "They hoped that evidence of a genetic cause would show that they had not caused it through any action or ...

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      Mentions: Genetics
    7. Common nerve protein elevated in aggressive neuroblastomas

      "Because of their neuronal origin, neuroblastomas synthesize and release neuropeptide Y (NPY), a small protein normally secreted from mature nerves. In previous research, Kitlinska and her colleagues have shown that NPY, acting via its Y2 and Y5 receptors (Y2R and Y5R), is crucial for maintaining neuroblastoma growth and protecting the tumors from chemotherapy.

      "To confirm the clinical relevance of our earlier work and assess NPY and its receptors as potential prognostic factors, we performed clinical study on tissue samples and serum from 87 neuroblastoma patients," Kitlinska explains.

      "We have found that NPY is released from aggressive neuroblastoma tumors into the ...

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    8. Efficient Killing of High Risk Neuroblastoma Using Natural Killer Cells Activated by Plasmacytoid Dendritic Cells.

      "Here, we developed a novel approach to improve the current anti-GD2 immunotherapy based on NK cell stimulation using toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDCs). We demonstrated that this strategy led to the efficient killing of NB cells. When the expression of GD2 was heterogeneous on NB cells, the combination of pDC-mediated NK-cell activation and anti-GD2 treatment significantly increased the cytotoxicity of NK cells against NB cells. Activation by pDCs led to a unique NK-cell phenotype characterized by increased surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with increased expression of CD69 on CD56dim cytotoxic cells, and strong ...

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      Mentions: Antibody Treatment
    9. Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

      "By the age of 45 years, the cumulative incidence of any pulmonary condition was 29.6% (95% CI, 29.1%-30.0%) for cancer survivors and 26.5% (95% CI, 24.9%-28.0%) for siblings. Fewer survivors reported ever smoking (23.6% vs 36.4%, P < .001), but survivors were more likely to report chronic cough (rate ratio [RR], 1.6; 95% CI, 1.4-1.9), oxygen need (RR, 1.8; 95% CI, 1.5-2.2), lung fibrosis (RR, 3.5; 95% CI, 2.3-5.4), and recurrent pneumonia (RR, 2.0; 95% CI, 1.4-3.0). The SMR ...

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    10. SPARC overexpression combined with radiation retards angiogenesis by suppressing VEGF-A via miR‑410 in human neuroblastoma cells.

      "In the present study, we demonstrate that overexpression of secreted protein acidic and rich in cysteine (SPARC) suppresses radiation induced angiogenesis in SK-N‑BE(2) and NB1691 neuroblastoma cells. We observed that overexpression of SPARC in SK-N-BE(2) and NB1691 cells reduced radiation induced angiogenesis in an in vivo mouse dorsal skin model and an ex vivo chicken CAM (chorioallantoic-membrane) model and also reduced tumor size in subcutaneous mouse tumor models of NB. We also observed that SPARC overexpression reduces VEGF-A expression, in SK-N-BE(2) and NB1691 NB cells via miR-410, a VEGF-A targeting microRNA. SPARC overexpression alone or in ...

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    11. Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy.

      "Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize ...

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      Mentions: Immunotherapy
    12. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

      "The first-in class ALK/c-MET/ROS1 inhibitor crizotinib (Xalkori) has shown remarkable clinical efficacy in treatment of ALK-positive NSCLC. In neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants ...

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      Mentions: ALK MYCN
    13. Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

      "All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu–melphalan (Mel) has been implemented in Europe and compared with Carboplatin–Etoposide ...

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      Mentions: Bone Marrow
    14. Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma.

      "Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and ...

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      Mentions: Treatment MYCN
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  3. Recent Quotes

    1. We wanted to remove an important barrier in using B cells as an antigen-presenting cell population, helping them complement or replace dendritic cells.
      By Gregory Szeto
    2. The antigen-presenting capabilities of B cells have often been underestimated, but they are being increasingly appreciated for their practical advantages in therapies.
      By Gail Bishop
    3. Our dream is to spawn out a whole class of therapies which involve taking out your own cells, telling them what to do, and putting them back into your body to fight your disease, whatever that may be.
      By Armon Sharei
    4. We envision a future system, if we can take advantage of its microfluidic nature, as a bedside or field-deployable device.
      By Armon Sharei
    5. Down the road, you could potentially get enough cells from just a normal syringe-based blood draw, run it through a bedside device that has the antigen you want to vaccinate against, and then you'd have the vaccine.
      By Gregory Szeto
    6. The problem is that unlike blood, a skin sample or even a tissue biopsy, you can't take a piece of a patient's neural system. It runs like complex wiring throughout the body and portions cannot be sampled for study.
      By Mick Bhatia
    7. Now we can take easy to obtain blood samples, and make the main cell types of neurological systems - the central nervous system and the peripheral nervous system - in a dish that is specialized for each patient.
      By Mick Bhatia
    8. If I was a patient and I was feeling pain or experiencing neuropathy, the prized pain drug for me would target the peripheral nervous system neurons, but do nothing to the central nervous system, thus avoiding non-addictive drug side effects.
      By Mick Bhatia
    9. This bench to bedside research is very exciting and will have a major impact on the management of neurological diseases, particularly neuropathic pain.
      By Akbar Panju
    10. The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases, Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform.
      By Prem Das