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Intrathecal administration of methotrexate (IT-MTX) can lead to neurotoxicity. MTX-induced neurotoxicity occasionally manifests with a stroke-like presentation that is difficult to distinguish from genuine stroke. We retrospectively reviewed records of nine patients with leukemia or lymphoma and episodes of stroke-like presentation at our institute between 2010 and 2015 for whom magnetic resonance imaging (MRI) data were available. Coagulation test results were compared between the two diagnostic groups. Four patients were diagnosed with MTX-induced stroke-like neurotoxicity. The first neurological event occurred 10-13 days after the fourth or later IT-MTX treatment. All four patients had hemiparalysis, two exhibited disturbed consciousness and three presented with speech disorders. Fibrin/fibrinogen degradation products (FDP) and D-dimer values were within normal ranges. MRI revealed bilateral lesions with restricted diffusion in all four cases. Neurological symptoms fluctuated and resolved within 5 days, and IT-MTX was subsequently re-initiated in all four cases. One patient developed transient hemiparalysis after a subsequent IT-MTX treatment, but this did not recur thereafter. Bilateral lesions on MRI and normal coagulation are indicative of MTX-induced stroke-like neurotoxicity. Continuation of IT-MTX after these events is generally feasible, but adverse event risk should be carefully weighed against anti-tumor benefits.

Approximately 20% of the pediatric acute myeloid leukemia (AML) cases show normal karyotypes without any recognizable cytogenetic alteration on conventional cytogenetic analysis. Recent state-of-th...

Patients with severe hypophosphatasia (HPP) develop osteogenic impairment with extremely low alkaline phosphatase (ALP) activity, resulting in a fatal course during infancy. Mesenchymal stem cells (MSCs) differentiate into various mesenchymal lineages, including bone and cartilage. The efficacy of allogeneic hematopoietic stem cell transplantation for congenital skeletal and storage disorders is limited, and therefore we focused on MSCs for the treatment of HPP. To determine the effect of MSCs on osteogenesis, we performed multiple infusions of ex vivo expanded allogeneic MSCs for two patients with severe HPP who had undergone bone marrow transplantation (BMT) from asymptomatic relatives harboring the heterozygous mutation. There were improvements in not only bone mineralization but also muscle mass, respiratory function, and mental development, resulting in the patients being alive at the age of 3. After the infusion of MSCs, chimerism analysis of the mesenchymal cell fraction isolated from bone marrow in the patients demonstrated that donor-derived DNA sequences existed. Adverse events of BMT were tolerated, whereas those of MSC infusion did not occur. However, restoration of ALP activity was limited, and normal bony architecture could not be achieved. Our data suggest that multiple MSC infusions, following BMT, were effective and brought about clinical benefits for patients with lethal HPP. Allogeneic MSC-based therapy would be useful for patients with other congenital bone diseases and tissue disorders if the curative strategy to restore clinically normal features, including bony architecture, can be established.

Background: Hematopoietic stem cell transplantation (HSCT) recipients carry a high risk of primary varicella and varicella-zoster virus (VZV) reactivation. VZV infections can be fatal, and VZV reactivation can be complicated by postherpetic neuralgia, which worsens the recipients’ post-HSCT quality of life. VZV vaccines may prevent such infections; however, international vaccination guidelines do not recommend VZV vaccination of HSCT recipients because few data regarding safety among HSCT recipients are available. In Japan, we use a high-titer Oka stain vaccine for varicella vaccination and zoster prevention in the elderly; the plaque forming unit (PFU) value of this vaccine is as high as the zoster vaccine used in the U.S. Data regarding the safety of zoster vaccine in HSCT recipients is limited; therefore, we report our experience with this high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients. Patients and Methods: Forty-seven pediatric allogeneic HSCT recipients who underwent transplantation at the Saitama Children’s Medical Center from 2000-2011 were vaccinated with live vaccines and their antibody titers were evaluated after vaccination. Among the 47 recipients, the Japanese high-titer varicella vaccine was administered to 32 recipients. Since establishing the live vaccine initiation criteria in 2009, allogeneic HSCT recipients were considered as recipients for live vaccines, including the varicella vaccine, if 24 months had passed after HSCT without active chronic GVHD or required immunosuppression. In addition, recipients were required to have a lymphocyte count >1500/μl or CD4 cell count >700/μl if they were 1000/μl or CD4 cell count >500/μl if they were >6 years, normal phytohemagglutinin response, and serum IgG level >500 mg/dL. Before 2009, time for vaccination depended on each doctor’s judgment. Patients were given a single dose of the Biken varicella vaccine containing a minimum of 23,000 PFUs. We use EIA to measure the antibody titer and defined seropositivity as a titer >6.0. The time to evaluate the antibody titer was not fixed. We retrospectively collected the clinical data of recipients and laboratory data by reviewing the medical records. Results: The 32 recipients, who received the Japanese varicella vaccine, underwent HSCT at a median age of 5.15 years (range: 0.5-16.4 years) and were vaccinated at a median of 20.65 months (range: 4.8-112.1 months) after HSCT. Twenty and 11 patients had received myeloablative and nonmyeloablative conditioning, respectively. Nine patients received related-donor transplant, of which eight were bone marrow and one was peripheral blood. Twenty-three patients received unrelated-donor transplant, of which 14 were bone marrow and nine were cord blood. Antithymocyte globulin was administered to four patients. Eighteen of the 32 patients (56.3%) were seropositive after vaccination. Of the 26 patients, whose vaccination histories and pre-transplantation histories were available, eight were affected by natural disease, six had been immunized, and 12 had not been immunized. At vaccination, the median lymphocyte count was 3201/μl (range: 817-6630/μl) and the median IgG value was 880 mg/dL (range: 233-1461 mg/dL). There was no significant risk factor associated with vaccine failure. We experienced one case of varicella because of wild type VZV and no cases of zoster after vaccination during a median follow-up period of 4.8 years (range: 0.4-11.3 years); the single patient developed varicella 13 days after vaccination, immediately after an influenza virus infection. Whereas, two cases of varicella and one case of zoster developed before vaccination. Of the other 15 recipients, who did not receive varicella vaccine, three varicella and two zoster developed in three recipients. Conclusion: We safely vaccinated pediatric allogeneic HSCT recipients with the Japanese high-titer varicella vaccine. This finding could encourage the use in the U.S. of zoster vaccines such as Zostavax@, which contains similarly high PFUs, and low-titer varicella vaccines such as Varivax@. However, the efficacy of high-titer varicella vaccines for preventing VZV reactivation in this population remains unclear. Further studies are warranted to elucidate the efficacy and difference between low-titer and high-titer varicella and zoster vaccines. Disclosures No relevant conflicts of interest to declare.