BackgroundTAFRO syndrome is a unique clinicopathologic variant of multicentric Castleman’s disease that has recently been identified in Japan. It is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, reticulin Fibrosis of the bone marrow, Renal dysfunction and Organomegaly (TAFRO). Previous reports have shown that affected patients usually respond to immunosuppressive therapy, but the disease sometimes has a fatal course. TAFRO syndrome occurs in the middle-aged and elderly and there are no prior reports of the disease in adolescents. Here we report the first adolescent case, successfully treated with anti-IL-6 receptor antibody (tocilizumab, TCZ) and monitored with serial cytokine profiles.Case presentationA 15-year-old Japanese boy was referred to us with fever of unknown origin. Whole body computed tomography demonstrated systemic lymphadenopathy, organomegaly and anasarca. Laboratory tests showed elevated C-reactive protein and hypoproteinemia. Bone marrow biopsy revealed a hyperplastic marrow with megakaryocytic hyperplasia and mild reticulin fibrosis. Despite methylprednisolone pulse therapy, the disease progressed markedly to respiratory distress, acute renal failure, anemia and thrombocytopenia. Serum and plasma levels of cytokines, including IL-6, vascular endothelial growth factor, neopterin and soluble tumor necrosis factor receptors I and II, were markedly elevated. Repeated weekly TCZ administration dramatically improved the patient’s symptoms and laboratory tests showed decreasing cytokine levels.ConclusionTo our knowledge, this is the first report of TAFRO syndrome in a young patient, suggesting that this disease can occur even in adolescence. The patient was successfully treated with TCZ. During our patient’s clinical course, monitoring cytokine profiles was useful to assess the disease activity of TAFRO syndrome.

Minimal residual disease (MRD) is derived from tumor-initiating cells (TICs) and is responsible for tumor relapse. Neuroblastoma is characterized by extreme tumor heterogeneity, and more than half of high-risk patients experience tumor relapse. To overcome tumor heterogeneity and achieve more sensitive detection of MRD, several sets of real-time RT-PCR markers have been reported for MRD monitoring in neuroblastoma patients from different centers. However, these markers vary across centers and are still being validated. In the present study, we validated the ability of 14 commonly used real-time RT-PCR markers to detect MRD based on their expression in neuroblastoma TICs, and we developed a novel MRD detection protocol, which scored the samples as MRD-positive when the expression of one of the 11 real-time RT-PCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) exceeded the normal range. By using this protocol, we prospectively monitored MRD in 73 bone marrow (BM), 12 peripheral blood stem cell and 8 peripheral blood samples from 14 neuroblastoma patients treated at a single center. We scored 100, 56, 56 and 57% BM cytology-positive, elevated vanillylmandelic acid (VMA), elevated homovanillic acid (HVA) and elevated neuron-specific enolase (NSE) samples as MRD-positive, respectively. MRD was also positive in 48, 45, 46 and 43% of the BM cytology-negative and normal VMA, normal HVA and normal NSE samples, respectively. These results suggest that the present MRD detection protocol based on the expression of a set of 11 real-time RT-PCR markers in neuroblastoma TICs achieves sensitive MRD monitoring in neuroblastoma patients.

The present results suggest that EGCG may inhibit the development of TICs in BE(2)-C cells.

Abstract. neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer deaths. Although retinoic acid (rA) is currently used to treat high-risk neuroblastoma patients in the clinic, rA-responsiveness is variable and unpredictable. since no alterations in the rA-signaling pathway have been found in neuroblastoma cells, molecules correlated with rA-induced differentiation will provide predictive markers of rA-responsiveness for clinical use. the rab family of small G proteins are key regulators of membrane traffic and play a critical role in cell differentiation and cancer progression. Although an increasing number of cancer-associated alternative splicing events have been identified, alternative splicing of rab proteins remains to be characterized in neuroblastoma. In the present study, we focused on rab15 that was originally identified as a brain-specific Rab protein and regulates the endocytic recycling pathway. We identified alternatively spliced rab15 isoforms designated as rab15 cn and rab15An in neuroblastoma cells. rab15 cn was composed of 7 exons encoding 212 amino acids and showed brain-specific expression. Alternative splicing of exon 4 generated rab15An that was predicted to encode 208 amino acids and was predominantly expressed in testis. rA induced neuronal differentiation of neuroblastoma BE(2)-C cells and specifically up-regulated rab15 cn expression. reciprocally, rA-induced differentiation was observed in rab15 cn -expressing Be(2)-c cells in preference to rab15An -expressing Be(2)-c cells. Furthermore, rab15 cn expression was also specifically up-regulated during rA-induced differentiation of newly established neuroblastoma cells from high-risk patients. these results suggest that rab15 expression correlates with rA-induced differentiation of neuroblastoma cells.

Severe congenital protein C (PC) deficiency is an autosomal recessive hereditary thrombophilia caused by mutations in PROC. The case manifested severe purpura fulminans, intracranial thrombosis or hemorrhage within 4 days after birth, resulting in blindness. We report the identification of inherited compound heterozygous mutations, including a novel nonsense mutation in PROC, and a prenatal genetic test for a subsequent pregnancy. Prenatal diagnosis may facilitate preemptive and radical therapy for severe PC deficiency.