Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon γ receptor 2 (IFNγR2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFNγ mediated immunity may predispose patients to SCC.

Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak–Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak–Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel–Lindau (Chuvash polycythemia), prolyl hydroxylase domain–containing protein-2, and hypoxia-inducible factor-2α (HIF-2α). Somatic gain-of-function mutations in the gene encoding HIF-2α were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2α protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2α activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak–Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak–Zhuang syndrome, even in male patients.

AKT plays a pivotal role in the signal transduction of cancer cells. MK2206, an AKT inhibitor, has been shown to be an effective anti-cancer drug to a variety of cancer cell lines. However, some cancer cells acquire resistance to MK2206 and new strategies to suppress these cell lines remain to be developed. Acquired MK-2206-resistant neuroblastoma (NB) cell sublines were induced by stepwise escalation of MK-2206 exposure (4–12 weeks). MTT assay was used to validate cell proliferation. Flow cytometry was performed for cell cycle analysis. Western blot assay was used for cell signaling study. MK2206 (5–10 µmol) significantly suppressed cell growth of MK2206 non-resistant NB cells (LAN-1, KP-N-SIFA, NB-19 and SK-N-DZ), but is less efficient in inhibiting that of resistant sublines, even after 2-week MK2206-free incubation. MK2206 acted in mTOR-S6K dependent and independent methods. MK-2206 resistant sublines (LAN-1-MK, KP-N-SIFA-MK, and SK-N-DZ-MK) showed lower IC50 of GSK2334470 (PDK1 inhibitor). The cell growth of all sublines was prohibited by AZD8805 (mTOR inhibitor), with IC50 of AZD8805 3–10 times lower than MK2206 non-resistant cells. The signaling profiles of these resistant sublines were characterized by elevated PDK1-mTOR-S6K activity, accompanying by low phosphorylation of AKT compared with non-resistant counterparts. GSK2334470 and AZD8055 effectively inhibited phosphorylation of PDK1 and mTOR, respectively, and induced higher G0–G1 ratio in LAN-1-MK than that in LAN-1 as well. PDK1 and mTOR inhibitors effected on phosphorylation of GSK3β in some of resistant sublines. NB cells can acquire MK2206 resistance after exposure for 4–12 weeks. Resistant cells feature reliance on PDK1-mTOR-S6K pathway and are more sensitive to PDK1 and mTOR inhibitors than the non-resistant counterparts. Thus, suppression of PDK1-mTOR-S6K signaling pathway is an effective way to overcome the MK2206 resistance, and this may be a promising strategy for targeted therapy.

In a previous study, we demonstrated that neuroblastoma subcutaneously implanted in immuno-competent mice is eliminated by intratumoral administration of neuroattenuated poliovirus (PV). Our results also suggested that the in vivo destruction of neuroblastoma cells by virotherapy lead to a robust antitumor immune response. In this work, splenocytes harvested from neuroblastoma-bearing animals treated with neuroattenuated PV exhibited significantly higher lytic activity against tumor target cells than did those from splenocytes derived from control mice. In vitro T-cell depletion experiments indicated that CD8+ T cells were essential for the cytotoxic antitumor activity of splenocytes. Moreover, adoptive transfer of splenocytes obtained from mice cured of neuroblastoma by PV virotherapy markedly delayed the tumor growth of previously established neuroblastomas in recipient naïve mice. These results confirmed that treatment with a neuroattenuated oncolytic PV strain induces antitumor immunity against neuroblastoma that is mainly mediated by cytotoxic CD8+ T cells. Immunocompetent mice, on the other hand, were immunized with PV-infected neuroblastoma cell lysate prior intravenous challenge with neuroblastoma cells. As a control, mice were vaccinated with either non-infected neuroblastoma cell lysate alone or mixed with PV, or with PBS prior tumor cell injection. Results showed that survival is significantly prolonged only in mice immunized with PV-infected tumor lysate. This finding clearly suggested that in vitro poliovirus infection of neuroblastoma cells turns these cells into a potent tumor immunogen. Further studies in oncolytic treatment of neuroblastoma using attenuated PV alone or in combination with immunotherapy with PV oncolysate should improve the probability for successful translation in the clinic.

Background/Aim: Huaier extract, whose main active constituent is the proteoglycan, has anti-tumor activity in several types of malignancies. In this study, we aimed to elucidate the effect of Huaier extract in hepatoblastoma cells. Materials and Methods: The effect of Huaier extract on the proliferation of human hepatoblastoma cell lines HepG2 and HuH-6, was examined. Results: Incubation with Huaier extract resulted in a marked, dose-dependent decrease in hepatoblastoma cell viability. Huaier extract induced S phase arrest in hepatoblastoma cells and upregulated the expression of the cell cycle related proteins cyclin D1 and cyclin D3. It also induced apoptosis in hepatoblastoma cells. Additionally, it significantly suppressed the activity of p-ERK and p-MEK. Conclusion: Huaier extract inhibits proliferation, and induces cell apoptosis and cell cycle arrest via the MEK-ERK pathway in hepatoblastoma cells. Huaier extract may act as a complementary agent for treating hepatoblastoma.