Pirarubicin Combination Low-Dose Chemotherapy for Early Infantile Stage MS Neuroblastoma: Case Report.

Neuroblastoma (NB) is a neural crest-derived malignant tumor which is diagnosed during infancy in approximately 40% of cases; spontaneous regressions are observed, but there are varying degrees of severity. Treatment is indicated if an infant's condition is at risk of deterioration. Herein, we report the case of a 42-day-old boy who presented with hepatomegaly and was diagnosed with stage MS NB. A pathological diagnosis of "poorly differentiated neuroblastoma with low mitosis-karyorrhexis index, favorable histology" was made; his tumor cells were hyperdiploid and MYCN was not amplified. Because he had respiratory distress caused by the rapidly evolving hepatomegaly, two cycles of chemotherapy containing vincristine and cyclophosphamide were administered in the second and fourth weeks of admission; however, his abdominal tumor did not shrink. In the sixth week of admission, chemotherapy was revised to pirarubicin and cyclophosphamide, and the tumor began to shrink. After discharge, there was no re-elevation of tumor markers; after 1 year, the hepatomegaly and liver metastases disappeared. During the 5-year follow-up, his growth and development were normal and he progressed without sequelae. A regimen that includes pirarubicin could merit further study in the treatment of early infants with stage MS low-risk NB who are at risk of complications.

Donor-derived myelodysplastic syndrome after allogeneic stem cell transplantation in a family with germline GATA2 mutation.

Germline GATA2 heterozygous mutations were identified as complex immunodeficiency and hematological syndromes characterized by cytopenia (monocytes, B-cells, NK-cells), susceptibility to mycobacterium, fungus, or Epstein-Barr virus (EBV) infection, and myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) development. Herein, we report a patient with AML who had a fatal infection after allogeneic hematopoietic stem cell transplantation (HSCT) due to impaired immune reconstitution associated with GATA2 mutation. A 15-year-old man was diagnosed with AML with monosomy 7. His family history was negative for immunodeficiency and hematological disorders. He attained complete remission after HSCT from an HLA-identical sister. Post-HSCT examinations performed 15 months later revealed pancytopenia, especially monocytopenia and the absence of B and NK cells, resulting in the occurrence of donor-type MDS. Twenty-one months after HSCT, he developed central nervous system aspergillosis and finally died of the disease. Two months later (24 months after PBSCT), the donor was diagnosed with persistent EBV infection accompanied by MDS with multilineage dysplasia. Genetic analysis of GATA2 revealed a novel heterozygous mutation (c.1023_1026dupCGCC) in both siblings. GATA2 mutations were highly prevalent among adolescent MDS/AML patients with monosomy 7. Therefore, the screening of GATA2 mutations in relatives is necessary when performing HSCT from a relative donor.

An 18-Year-Old Male With X-linked Lymphoproliferative Syndrome Type 1 Who Developed Primary Central Nervous System Lymphoma 6 Months After Primary Epstein-Barr Virus Infection.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.

Impact of sirolimus treatment for refractory kaposiform hemangioendothelioma with exacerbation of the disease 10 years after initial diagnosis.

We describe our experience with a 12 year-old girl with kaposiform hemangioendothelioma accompanied by Kasabach-Merritt phenomenon with exacerbation of the disease 10 years after the initial diagnosis. Kaposiform hemangioendothelioma infiltrated into the subcutaneous tissue of the facial skin with deterioration of coagulopathy despite conventional therapies including corticosteroid, vincristine, and propranolol. Sirolimus, a mammalian target of rapamycin inhibitor, produced rapid and dramatic improvement of the Kasabach-Merritt phenomenon and kaposiform hemangioendothelioma shrinkage. Eventually, multifocal lesions of kaposiform hemangioendothelioma disappeared on the images of magnetic resonance imaging and have remained in remission for 27 months after sirolimus cessation. We demonstrated that the AKT/mammalian target of rapamycin signaling pathway played a pivotal role in the kaposiform hemangioendothelioma growth. Sirolimus must be a strong candidate for molecular therapy targeting kaposiform hemangioendothelioma.

Appropriate modulation of autophagy sensitizes malignant peripheral nerve sheath tumor cells to treatment with imatinib mesylate.

Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 µM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.