Evaluation of Aromaticity for Open-Shell Singlet Dicyclopenta-Fused Acenes and Polyacenes Based on a Magnetically Induced Current.

The aromaticity of dicyclopenta-fused acenes (DPAs) and polyacenes (PAs) of increasing size has been studied by evaluation with the GIMIC method at the DFT level of the magnetically-induced currents (MICs), and by analyzing their spatial distributions. For these open-shell singlet molecules, spin-restricted and -unrestricted treatments provide very different MICs, the latter ones providing the most reliable solution. These MICs and the differences between spin-restricted and -unrestricted treatments are interpreted in terms of the bond current strengths and the current gradients, which indicate the bond aromaticity and enable the spatial distributions of the diatropic and paratropic currents to be analyzed, respectively. In particular, they allow the rationalization of the MICs in correlation with the odd-electron density distributions and their diradical characters. These calculations demonstrate that 1) in increasingly large PAs the bond current strengths get smaller and smaller than in benzene and get almost similar in the central and terminal rings, 2) for DPAs the MICs increase from dominant paratropic currents and antiaromaticity in the small compounds to diatropic currents and aromaticity in the larger ones, and 3) in the largest DPAs, the central rings are characterized by large diatropic currents and the terminal five-membered rings, for which the odd-electron densities are localized by weak ones.

Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine.

BACKGROUND: Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS). PROCEDURE: We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009. RESULTS: For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%-54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%-98.7%) with a median follow-up period of 103 months (range, 29-221 months). CONCLUSIONS: Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.

A Pediatric Case of Metastatic Conventional Parosteal Osteosarcoma Treated With Multidrug Chemotherapy.

Parosteal osteosarcoma (POS) is conventionally a low-grade sarcoma with limited metastatic potential; however, the tumor occasionally transforms into a high-grade dedifferentiated POS, which commonly metastasizes to distant organs. The present report describes a rare pediatric case of conventional POS with no dedifferentiated component yet had multiple pulmonary metastases at initial diagnosis. Following limb-sparing surgery and osteosarcoma-oriented neoadjuvant chemotherapy, the patient received total resection of pulmonary metastases. Despite no treatment for pulmonary recurrence 1 year after adjuvant chemotherapy, the patient is alive with stable disease 4 years and 6 months after the initial diagnosis.

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

Rituximab-combination chemotherapy achieves a 10th cycle of remission for Burkitt's lymphoma.

A 14-year-old girl with multiple intra-abdominal tumors was diagnosed with stage III Burkitt's lymphoma. She achieved complete remission after multi-drug chemotherapy, but she relapsed after six courses. Autologous peripheral blood stem cells (PBSC) or allogeneic PBSC harvested from an HLA-identical sibling were insufficient, and her family did not agree to bone marrow collection from the sibling. Although the patient relapsed nine times (the relapses involved intra-abdominal organs or bone) during the following 4 years 7 months, treatment with rituximab monotherapy or in combination with ifosphamide, carboplastin, and etoposide, or local irradiation (33.8-40.0 Gy) to treat the bone metastases, proved effective, resulting in complete or partial remission. At the time of writing, the patient was in a 10th cycle of remission lasting 1 year 6 months and had not required transplantation. Thus, a chemotherapy regimen including rituximab might be effective for Burkitt's lymphoma in patients experiencing multiple relapse.

Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma.

A 5-year-old boy with glioblastoma relapsed soon after postoperative irradiation in combination with temozolomide. Second-line chemotherapy was also ineffective; therefore, the bevacizumab and irinotecan were given after a third gross-total resection of the tumor. Treatment was interrupted for 1 month due to development of posterior reversible encephalopathy syndrome, but was re-initiated at a lower dose of bevacizumab with prolonged intervals between treatments. The patient was alive and disease free 2 years after initial diagnosis. Bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis.

Prognostic significance of aminopeptidase-N (CD13) in hepatoblastoma.

BACKGROUND: Hepatoblastoma is a rare childhood malignant tumor that originates from immature hepatic cells. Aminopeptidase-N(CD13), an ectopeptidase that promotes tumor invasion and metastasis, is expressed in fetal stage hepatic progenitor cells, although its role in hepatoblastoma remains unclear. METHODS: The expression pattern of CD13 was investigated on immunohistochemistry in 30 tissue samples from 27 hepatoblastoma patients (16 with predominantly embryonal [pE] histology and 14 with predominantly fetal [pF] histology). Immunoreactive score (IRS) was used to quantify staining data, and the relationship between CD13 expression, clinicopathological factors, and clinical outcome was investigated. The biological function of CD13 was also examined in the hepatoblastoma cell lines Huh6 and HepG2. RESULTS: All specimens stained positive for CD13, with higher CD13 expression in pE than in pF hepatoblastoma samples (median IRS, 4; range, 2-9 vs 2; range, 1-4). Strong CD13 expression was correlated with vascular invasion. Five year event-free survival and overall survival were better in patients with CD13(low) than in those with CD13(high) tumors (100% vs 51.0%, P = 0.026; and 100% vs 74.0%, P = 0.114, respectively). A CD13-neutralizing antibody and the potent CD13 inhibitor, Ubenimex, suppressed invasive activity in HepG2 cells in vitro. CONCLUSIONS: CD13 expression is associated with hepatoblastoma invasiveness and could be a novel prognostic marker for hepatoblastoma.

Development of CMV retinitis in an antigenemia-negative infant after cord blood transplantation.

A five-month-old male infant with familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation using reduced-intensity conditioning. Methylprednisolone (mPSL) pulse administration was performed for marked pulmonary edema during the early phase of transplantation, followed by GVHD treatment with mPSL until day 100. CMV antigenemia was detected on days 27 and 55, but serum became negative with 2- to 3-week ganciclovir (GCV) treatment on both occasions. On day 120, ophthalmological findings included multiple bilateral white spots and a positive PCR study using anterior chamber fluid confirmed the diagnosis of CMV retinitis affecting both eyes, although CMV antigenemia was negative. Re-treatment with GCV had a minimal effect on the ophthalmological findings, while foscarnet administration markedly improved the retinitis and decreased the CMV-DNA level. Considering that a substantial proportion of patients develop CMV retinitis even when CMV antigenemia is not present, routine monitoring involving ophthalmological examinations should be conducted for hematopoietic transplant patients, especially infants, who cannot complain of ocular symptoms.

Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis.

HAX1 was identified as the gene responsible for the autosomal recessive type of severe congenital neutropenia. However, the connection between mutations in the HAX1 gene and defective granulopoiesis in this disease has remained unclear, mainly due to the lack of a useful experimental model for this disease. In this study, we generated induced pluripotent stem cell lines from a patient presenting for severe congenital neutropenia with HAX1 gene deficiency, and analyzed their in vitro neutrophil differentiation potential by using a novel serum- and feeder-free directed differentiation culture system. Cytostaining and flow cytometric analyses of myeloid cells differentiated from patient-derived induced pluripotent stem cells showed arrest at the myeloid progenitor stage and apoptotic predisposition, both of which replicated abnormal granulopoiesis. Moreover, lentiviral transduction of the HAX1 cDNA into patient-derived induced pluripotent stem cells reversed disease-related abnormal granulopoiesis. This in vitro neutrophil differentiation system, which uses patient-derived induced pluripotent stem cells for disease investigation, may serve as a novel experimental model and a platform for high-throughput screening of drugs for various congenital neutrophil disorders in the future.

First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy.

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992-1999 versus 2000-2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.

Salvage allogeneic stem cell transplantation in patients with pediatric myelodysplastic syndrome and myeloproliferative neoplasms.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable approach for myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN); however, the event-free survival rate of patients with pediatric MDS and MPN is still only approximately 60%. Although salvage HSCT is the only curative approach for patients with the failure of previous HSCT, its safety and efficacy have yet to be determined. PROCEDURES: We retrospectively analyzed 51 pediatric MDS or MPN who received salvage HSCT for relapse or graft failure following HSCT using registry data of the Japan Society for Hematopoietic Cell Transplantation. The indications used for salvage HSCT were relapse in 22 patients and graft failure in 29 patients. RESULTS: The overall survival (OS) rate for salvage HSCT in relapsed patients was 49.0 ± 10.8% at 3 years. The cumulative incidence of relapse following salvage HSCT was 29.8 ± 10.7% at 3 years, whereas the incidence of non-relapse mortality (NRM) was 28.6 ± 10.2%. No significant differences were observed in the OS after salvage HSCT between disease types. Twenty-four of 29 patients who received salvage HSCT for graft failure achieved engraftment, resulting in an engraftment probability of 81.5 ± 8.0% on day 100. The OS rate after salvage HSCT for graft failure was 56.8 ± 9.6% at 3 years. CONCLUSIONS: Second HSCT should be considered as a valuable option for the patients with relapse and graft failure in patients with pediatric MDS or MPN after HSCT, but high NRM is an important issue that needs to be addressed.

An endobronchial inflammatory myofibroblastic tumor in a 10-yr-old child after allogeneic hematopoietic cell transplantation.

IMTs belong to the group of soft tissue tumor and could occur at any anatomical site; however, the causes and growth feature remain unclear. This case report documents a 10-yr-old male suffering from slowly developing dyspnea on exertion and cough around seven months post-HCT. He was diagnosed with an endobronchial tumor based on imaging, and histology confirmed ALK-positive submucosal spindle-shaped cells with infiltrative cells, compatible with IMT. We should be aware that IMT is a potential complication of pediatric allogeneic HCT and can cause sudden airway obstruction.

The clinical utility of genetic testing for t(8;16)(p11;p13) in congenital acute myeloid leukemia.

Acute myeloid leukemia (AML) with t(8;16)(p11;p13) is known to have very poor prognosis in adults. In contrast, the prognosis is not clear in pediatric patients and chemotherapy is generally started immediately in cases of congenital leukemia because of its association with hyperleukocytosis and poor prognosis. This study reports a case of congenital AML where chemotherapy was discontinued after detection of a MOZ-CBP fusion, which remains in remission without additional treatment. This article stresses the importance of examination for the presence of the MOZ-CBP fusion at diagnosis to inform treatment decisions in congenital AML.

Longitudinal nutritional assessment in acute lymphoblastic leukemia during treatment.

BACKGROUND: A nutritional assessment of pediatric patients with cancer is important to improve their outcome. The number of longitudinal nutritional studies during treatment, however, is limited. The purpose of this study was to investigate the longitudinal changes in anthropometric measures and serum albumin level during chemotherapy in patients with acute lymphoblastic leukemia (ALL). METHODS: We retrospectively reviewed the charts of 23 patients (19 boys, four girls) with ALL from April 2007 to March 2010. The median age at diagnosis was 4.5 years. Bodyweight, height, and serum albumin levels were measured at the start and the end point of each chemotherapy phase. RESULTS: At diagnosis, two patients (8.7%) were underweight and five patients (21.7%) were overweight according to body mass index z-score, while five patients were underweight and three (13.0%) were overweight according to Waterlow score. The prevalence of malnourished patients did not change significantly throughout chemotherapy by either assessment. The absolute scores in either assessment were significantly reduced at the sanctuary treatment phase. Low serum albumin (<3.2 g/dL) was found in two patients at diagnosis. Mean albumin decreased significantly at the induction and the re-induction phases. CONCLUSIONS: Given that nutritional status under a similar chemotherapeutic regimen as assessed by anthropometric measures and albumin level differed among patients, careful observation of the nutritional status and intervention may be necessary at different phases of chemotherapy.

Acute lymphoblastic leukemia in a girl with Wilson's disease.

Wilson's disease (WD) is an autosomal recessive defect in cellular copper transportation. Although acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy, only two cases of ALL associated with WD have been reported to date. One patient died of relapse and infection, and the other died of neutropenic sepsis during the treatment. We here describe the case of a 10-year-old girl with WD and ALL. Adverse events of chemotherapy, including liver toxicity and severe myelosuppression, necessitated adjustments in the chemotherapy doses. After completion of the treatment, the patient has remained in remission from ALL without progression of liver damage for 2 years. Severe treatment-related toxicity should be considered in chemotherapy for patients with WD.

Perforation of enteric duplication during chemotherapy for osteosarcoma.

A 9-year-old boy undergoing chemotherapy for conventional osteosarcoma complained of severe abdominal pain associated with rebound tenderness and muscular defense. Abdominal computed tomography indicated intraperitoneal free air. On surgical investigation, a diverticulum-like lesion, perforated at the base, was found on the sidewall of the ileum. The anatomic location of the lesion was indicative of enteric duplication. Although the frequency of complications is very rare, perforations of the digestive tract should be considered in patients suffering severe abdominal pain while receiving chemotherapy.

[Epileptic encephalopathy associated with human herpes virus 6 (HHV-6) encephalitis after the second cord blood transplantation in a patient with pediatric acute lymphoblastic leukemia].

The incidence of HHV-6 encephalitis during hematopoietic stem cell transplantation (HSCT) in children is thought to be less than that in adults and risk factors, prognosis and complications are virtually unknown. Herein, we report a pediatric case developing epileptic encephalopathy following HHV-6 encephalitis after a second cord blood transplantation (CBT). A 7-year-old boy with relapsed B-precursor acute lymphoblastic leukemia in second remission underwent CBT. However, he received a second CBT due to graft failure. On day 25 after the second CBT, he developed short-term memory defects and seizures. He was diagnosed with HHV-6 encephalitis because HHV-6 DNA was detected in his blood and cerebrospinal fluid and abnormal hippocampal signals were seen on cranial magnetic resonance imaging (MRI). After treatment with foscarnet, HHV-6 DNA levels and MRI findings improved; however, he developed epileptic encephalopathy five months after the onset of encephalitis. There are very few reports on pediatric epileptic encephalopathy associated with HHV-6 encephalitis after HSCT. Detailed studies are needed to analyze risk factors, prognosis, and complications.

Adipocytokines in childhood cancer survivors and correlation with metabolic syndrome components.

BACKGROUND: Although there are several studies on the prevalence of metabolic syndrome (MetS) in childhood cancer survivors (CCS), the association between MetS components and serum adipocytokine level has not been elucidated. METHODS: The charts of 49 patients (27 male, 22 female) who had attended the CCS clinic of the Department of Pediatrics, Kyoto University Hospital, between April 2009 and March 2010 were retrospectively reviewed. Median age was 10.7 years, and the median interval since the completion of chemotherapy was 5.1 years. The diagnosis of MetS was made based on the Japanese criteria for either children or adults. RESULTS: Three (6.1%) of 49 patients fulfilled the criteria for MetS, and 28 (57.1%) had at least one component of MetS. High leptin level was seen in 18 patients (36.7%), and low total adiponectin level was seen in 20 (40.8%). The number of patients with high leptin was correlated with body mass index z-score (>2.0), abdominal circumference/height (≥0.5), diastolic blood pressure and fasting blood sugar. The number of patients with low total adiponectin was correlated with systolic blood pressure and triglyceride. When the patients were divided into three groups based on the number of positive MetS components (0, 1 and 2-4), leptin and adiponectin tended to be higher and lower in the third group, respectively. CONCLUSIONS: Adipocytokines may play a role in the pathogenesis of MetS occurring in CCS. It is recommended that adipocytokines be evaluated together with MetS components at the CCS follow-up clinics.

[Utility of endoscopic ultrasound-guided fine needle aspiration for diagnosis of Burkitt lymphoma in two pediatric cases].

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed as a diagnostic procedure for two pediatric patients with intra-abdominal tumors. Case 1 was an 8-year-old boy with a huge tumor in the portal-hepatic region. Case 2 was a 17-year-old girl with a history of diabetes and recurrent relapse of Burkitt lymphoma, who had a newly developing tumor in the pancreatic body. In both cases, EUS-FNA was performed as a less invasive diagnostic procedure than open biopsy or total resection of the tumor. Tumor cells were determined to be of the B cell lineage by flow cytometric and immunostaining analyses. Both cases were diagnosed as having Burkitt lymphoma based on detection of IgH/C-MYC translocation by FISH. The aspiration was successfully conducted without severe complications, and both patients were immediately given chemotherapy. EUS-FNA is a safe and minimally invasive procedure with high diagnostic value for pediatric cases with intra-abdominal tumors.

Correlations between atrophy of the entorhinal cortex and cognitive function in patients with Alzheimer's disease and mild cognitive impairment.

AIMS: In order to confirm the utility of the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) in assessing the atrophy of the entorhinal cortex, we investigated whether there were correlations between VSRAD and the scores of neuropsychological tests in the patients with Alzheimer's disease (AD) and mild cognitive impairment. METHODS: Thirty patients, including 18 AD and 12 mild cognitive impairment patients, were included in this study. VSRAD was performed to assess the atrophy of the entorhinal cortex. The patients were carefully screened with the neuropsychological tests, including Wechsler Adult Intelligence Scale-III (WAIS-III), the Wechsler Memory Scale-Revised, the Alzheimer's Disease Assessment Scale-Cognitive Part (ADAS-cog) and the revised version of Hasegawa's Dementia Scale. RESULTS: All patients showed atrophy with different degrees in the entorhinal cortex except one case. Z-scores had significant positive correlation with ADAS-cog, and negative correlation with Information subset of WAIS-III (respectively, P = 0.0129 and P = 0.0294). The revised version of Hasegawa's Dementia Scale and the Similarities subsets of the WAIS-III had a tendency of negatively correlating with Z-scores of VSRAD (respectively, P = 0.0532 and P = 0.0635). The Delayed Visual Reproduction subset of the Wechsler Memory Scale-Revised was also found to have a weak negative correlation with Z-scores (P = 0.0609). CONCLUSIONS: Z-scores of VSRAD were revealed to have a close relation with many neuropsychological tests, especially ADAS-cog and the Information subset of WAIS-III. The results meant that VSRAD was a useful indictor of early diagnosis of AD, closely correlating with the changes of cognitive functions and the progression of the disease.