Genotypes versus phenotypes: The potential paradigm shift in the diagnosis and management of pediatric neoplasms.

The gold standard of cancer diagnosis has long been based on histological characteristics. With the rapid advancement of genetic medicine, such standard algorithm of diagnostic approach is facing a challenge. The genetic findings have been changed from being a "supporting character" into the role of a "main character". More and more disease diagnosis and classification has to be defined by genetic basis. In this article, we focus on the challenges in the field of pediatric oncology. We cited 2 scenarios where genetic information plays a pivotal role in identifying the underlying pathology. The first scenario is that same genetic mutation can lead to variable clinical phenotypes, this includes EWSR1-PATZ1 fusion related neoplasms; BCOR neoplasms; and GATA-2 deficiency related immunodeficiency and myelodysplastic syndrome. Another scenario is relatively more common that is the same clinical and histopathological phenotype with different underlying genotypes. The genotypes actually impact on the treatment response and outcome. We used medulloblastoma as an example. In fact, we can also find similar scenario in many pediatric cancers such as Ewing sarcoma, ependymoma, etc. The essence of this article is to remind clinicians of the rapid development in genetic medicine and it has been reshaping the landscape of the modern disease classification and therapeutic approach. In the near future, it may even lead to a paradigm shift in our disease diagnostic algorithm.

Challenges and opportunities for managing pediatric central nervous system tumors in China.

Central nervous system (CNS) tumors represent the most deadly cancer in pediatric age group. In China, thousands of children are diagnosed with CNS tumors every year. Despite the improving socioeconomic status and availability of medical expertise within the country, unique challenges remain for the delivery of pediatric neuro-oncology service. In this review, we discuss the existing hurdles for improving the outcome of children with CNS tumors in China. Need for precise disease burden estimation, lack of intra- and inter-hospital collaborative networks, high probability of treatment abandonment, along with financial toxicities from treatment represent the key challenges that Chinese healthcare providers encounter. The tremendous opportunities for advancing the status of pediatric neuro-oncology care in and beyond the country are explored.

Bismuth Porphyrin Antagonizes Cisplatin-Induced Nephrotoxicity via Unexpected Metallothionein-Independent Mechanisms.

Cisplatin (CDDP) has been a highly successful anticancer drug in cancer therapy; however, its further application suffers severe nephrotoxicity. Herein, we identify bismuth tetraphenylporphyrinate [Bi(TPP)] as a potent protective agent against CDDP-induced nephrotoxicity. Bi(TPP) attenuates CDDP-induced acute kidney injury and prevents the death of mice exposed to a lethal dose of CDDP. The protective potency of bismuth porphyrin complexes could be optimized by varying lipophilic TPP ligands with ideal ClogP values of 8-14. Unexpectedly, Bi(TPP) exhibited a protective role via metallothionein-independent pathways, i.e., maintenance of redox homeostasis and energy supplement, elimination of accumulated platinum in the kidney, and inactivation of caspases cascade in apoptotic pathway. Significantly, Bi(TPP) does not compromise the antitumor activity of CDDP in the orthotopic tumor xenograft mouse model. These findings suggest that Bi(TPP) could be incorporated into current CDDP-based cancer therapy as a nephroprotective agent.

Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment.

BACKGROUND: Relapsed T-lineage acute lymphoblastic leukemia (T-ALL) has been an incurable disease. Recent reports showed that an L-arginine depleting enzyme, pegylated arginase (BCT-100) may be effective against T-ALL cells. On the other hand, studies including ours had shown the symbiosis of ALL blasts and human mesenchymal stromal cells (hMSCs) in bone marrow microenvironment during L-asparaginase treatment. As L-asparaginase and BCT-100 both act by depleting lymphoid cells of specific amino acid, we hypothesized that hMSCs may also protect T-ALL blasts from BCT-100 treatment in co-culture and such protection may be abrogated by pre-treating hMSCs with vincristine (VCR). METHODS: XTT assay was used to test sensitivities of T-ALL cell lines and hMSCs to BCT-100. Apoptosis of T-ALL cell lines with or without BCT-100 treatment were tested by annexin V / propidium iodide (AV/PI) assay using flow cytometer. Western blotting was performed to analyze the expression of ornithine transcarbamylase (OTC), an enzyme involved in L-arginine metabolism which may account for BCT-100 resistance. RESULTS: hMSCs were resistant to BCT-100 while CCRF-CEM, Jurkat and MOLT-4 were very sensitive to it. hMSCs could protect all the three cell lines from BCT-100 treatment in transwell co-culture. All the 3 T-ALL cell lines were also found to be rescued by an L-arginine precursor citrulline, while the breakdown product of BCT-100, ornithine only had limited salvaging effect on CCRF-CEM but not Jurkat and MOLT-4. Both hMSCs and 3 T-ALL cell lines express citrulline synthesis enzyme, ornithine transcarbamylase (OTC) at basal level while only hMSCs could express OTC at relatively higher level under BCT-100 treatment. Treating hMSCs with vincristine before co-culturing with T-ALL could resume the cytotoxicity of BCT-100 to CCRF-CEM and MOLT-4 cells. CONCLUSIONS: Our results suggest a possible strategy to overcome resistance to BCT-100 from cancer microenvironments by suppressing hMSCs either in marrow or in the perivascular niche using vincristine.