Abstract: Global seabird populations are in decline, with nearly half of all seabird species currently in an extinction crisis. Understanding long-term seabird population trends is an essential first step to inform conservation actions. In this study, we assembled historical breeding records of seabirds throughout the Japanese archipelago and quantified the long-term population trends of 10 major breeding seabird species using a hierarchical Bayesian state-space model. The model revealed that six species had increasing or no detectable trends (Short-tailed Albatross Phoebastria albatrus , Leach’s Storm Petrel Oceanodroma leucorhoa , Pelagic Cormorant Phalacrocorax pelagicus , Japanese Cormorant Phalacrocorax capillatus , Spectacled Guillemot Cepphus carbo, and Rhinoceros Auklet Cerorhinca monocerata ). However, decreasing trends were found not only in nationally threatened species (Common Murre Uria aalge , and Tufted Puffin Fratercula cirrhata ) but also common species that are often described as abundant (Black-tailed Gull Larus crassirostris and Slaty-backed Gull Larus schistisagus ). These declining species have declined to 3–35% of baseline levels over the past 30 years. This study provides the first evidence of long-term declines in common and widespread seabirds in Japan.

Abstract: Abstract 1451 Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). In DS-associated ALL (DS-ALL), the chromosome aberrations which are generally common in childhood ALL, such as hyperdiploidy and t(12;21), are less frequent. Recent studies have shown that activating JAK2 mutations and overexpression of cytokine receptor-like factor 2 (CRLF2) gene are identified in approximately 20% and 50–60% of DS-ALL in Western countries, respectively. Most of the patients with CRLF2 overexpression have been reported to be associated with interstitial deletions of the pseudoautosomal region 1 (PAR1) of the sex chromosomes and the P2RY8-CRLF2 fusion gene. In addition, one report showed that the activating CRLF2 F232C mutation was identified in about 10% of DS-ALL. However, there have been no studies to determine the incidence of these genetic aberrations in Asian patients with DS-ALL. In this study, 23 patients with DS-ALL in Japan were screened for mutations in the pseudokinase domain of the JAK2 gene, the P2RY8-CRLF2 fusion gene, and the CRLF2 F232C mutation by PCR/RT-PCR and direct sequencing. Fourteen patients, whose bone marrow RNAs were available, were also screened for CRLF2 overexpression by real-time quantitative RT-PCR. We identified the JAK2 R683G mutation in 2 patients (9%) and the P2RY8-CRLF2 fusion gene in 4 patients (17%). The CRLF2 F232C mutation was not detected in any patient. CRLF2 overexpression was observed in 2 of 14 patients examined (14%). Although bone marrow RNA was available in only 1 of 4 patients positive for P2RY8-CRLF2, high-level expression of CRLF2 was confirmed in this patient. The other patient with CRLF2 overexpression was negative for P2RY8-CRLF2, indicating the involvement of the other type of CRLF2 rearrangement, IGH@-CRLF2 in this patient. We also performed a preliminary study on JAK1, JAK3, and Interleukin-7 receptor-α (IL7R) mutations, and 14, 11, and 12 patients were screened for mutations in the pseudokinase domain of JAK1, JAK3, and exon 5 and 6 of IL7R, respectively. However, no mutations were identified in any patient. Our results show the lower incidence of CRLF2 rearrangements in DS-ALL patients in Japan than that in Western countries. Gene alterations other than CRLF2 rearrangements may contribute to leukemogenesis in Japanese patients with DS-ALL. To clarify if the incidences of the mutations in JAK1-3, CRLF2, and IL7R are also lower in DS-ALL patients in Japan than those in Western counties, more patients need to be studied. Disclosures: No relevant conflicts of interest to declare.

Abstract: X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a developmental and immunologic disorder caused by hypomorphic mutations in the nuclear factor-κB essential modulator (NEMO) gene. NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which phosphorylates and degrades NF-κB inhibitor α (IκBα), causing NF-κB activation. Following the identification of amorphic NEMO mutations causing familial incontinentia pigmenti (IP), hypomorphic mutations in NEMO have been identified in XL-EDA-ID patients. Affected boys are susceptible to infections with various microorganisms, mostly pyogenic bacteria and mycobacteria. Stem cell transplantation (SCT) is thought to be the only curative treatment, but successful SCT has not yet been reported. We here report the first successful treatment of the disorder by SCT. The patient was a 3-year-old boy. His mother and maternal grandmother had been diagnosed with IP. He had frequent episodes of enterocolitis, and Enterobacter aerogenes sepsis. Mutation analysis revealed NEMO mutation (1167 insC) in both the patient and his mother. Flow cytometry analysis showed lower NEMO expression in each PBMC lineage, and CD40L induced less up-regulation of CD23, CD54, CD86, and CD95 in the patient’s cells. The patient did not have an HLA-matched related or unrelated bone marrow donor. At 3 years of age, an unrelated UCSCT was performed after written consent was obtained from his parents. Pretransplant conditioning consisted of fludarabin (30 mg/m2/d) from day -7 to day -3, melpharan (70 mg/m2/d) from day -6 to day -5, and rabbit anti-T-lymphocyte globulin (ATG) (2.5 mg/kg/d) from day -5 to day -1. The patient received 4.6 × 107 total nucleated cells/kg from a male donor. The recipient and donor were one antigen mismatched by serology and four loci mismatched by DNA typing. Following uneventful engraftment, NEMO protein expression was normalized and cytokine response was significantly improved. Lineage-specific genetic analysis confirmed full donor chimerism. Six months after UCSCT, the patient is in perfect performance status. This outcome shows that correction of immunodeficiency associated with NEMO mutation is possible by SCT, and UCSCT with a reduced-intensity regimen can be a suitable therapy for affected patients.

Abstract: Background: More than 65% of patients (pts) with extranodal natural killer/T-cell lymphoma, nasal type (ENKL) have localized disease at diagnosis, and sites of ENKL involvement are confined to the nasal cavity and paranasal sinuses in most pts. Chemoradiotherapy with non-anthracycline-containing chemotherapy (eg, radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin; RT-DeVIC) has improved the prognosis of pts with localized nasal ENKL and is regarded as the current standard approach. It is known that pts in the NK/T-cell lymphoma prognostic index (NK-PI) Group 3/4 is at a high risk of central nervous system (CNS) relapse in the CHOP era; however, the incidence and risk factors for CNS relapse with localized ENKL in the non-anthracycline era are not well known. In particular, it is unclear whether CNS relapse is more frequent in the pts with involvement adjacent to the skull base. Methods: A dataset of our recent study (NKEA Part A, UMIN000015491) was used for analysis. We retrospectively analyzed data from pts with newly diagnosed localized nasal ENKL who were diagnosed at 31 institutes in Japan between 2000 and 2013. Pts with extranasal ENKL, those having distant lymph node involvement and/or CNS involvement at diagnosis, and those who received anthracycline chemotherapy were excluded. The incidence and risk factors for CNS relapse in the following two cohorts were analyzed: pts who received non-anthracycline therapy (n = 189) and pts treated with RT-(2/3)DeVIC (n = 165). The time to CNS relapse in this study was defined as the time from the diagnosis to disease progression with CNS involvement and treatment failure with CNS relapse after complete response. Univariate and multivariate analyses included the following parameters: male sex, age at diagnosis 〉 60 years, B symptoms, ECOG PS 〉 1, high-risk NK-PI (Group 3/4), the high-risk group of the prognostic index of NK lymphoma (PINK), C-reactive protein 〉 upper limit of normal (ULN), serum soluble IL-2 receptor (sIL-2R) 〉 ULN, detectable EBV-DNA in peripheral blood, lymphocyte count 〈 1,000 /mL, hemoglobin 〈 11 g/dL, platelet count 〈 150 x 103 /mL, lactate dehydrogenase 〉 ULN, albumin 〉 ULN, the presence of each site of lymphomatous involvement (paranasal sinuses, palate, orbit, gingiva, facial skin, Waldeyer's ring, and regional lymph nodes), CNS prophylaxis (intrathecal administration of methotrexate and/or cytarabine), and the use of RT-DeVIC. In 84 pts, pretreatment CT, MR, or PET-CT was centrally reviewed and evaluated the primary tumor invasion by two radiation oncologists. Subsequently, the relationship between the involvement of paranasal sinus and CNS relapse was analyzed. Results: Of the 189 pts with localized nasal ENKL who received non-anthracycline therapy, the median age was 55 years (range: 16-83 years) and 34% were 〉 60 years old. The baseline clinical features were as follows: male, 71%; stage II, 28%; lymph node involvement, 21%; elevated LDH, 27%; ECOG PS 〉 1, 8%; B symptom present, 34%; elevated serum sIL-2R, 39%; and NK-PI high-risk, 22%. The most common site of involvement was the nasal cavity (93%) followed by the paranasal sinuses (27%), palate (6%), orbit (6%), and gingiva (2%). Fifteen pts received CNS prophylaxis. With a median follow-up of 5.8 years, the 5-year OS and PFS were 74% and 64%, respectively. The 2-year and 5-year CNS relapse rates were 5.1% and 7.2%, respectively. During the follow-up, 12 pts experienced CNS relapse. The NK-PI group 3/4 and elevated serum sIL-2R were not associated with CNS relapse in a univariate analysis. A multivariate analysis identified the involvement of the gingiva (HR, 16.74; 95% CI, 3.49-80.23) and that of the palate (HR, 6.27; 95% CI, 1.66-23.77) as independent risk factors for CNS relapse. In pts treated with RT-(2/3)DeVIC, multivariate analysis identified the involvement of the gingiva (HR, 40.28; 95% CI, 7.25-223.77) and the paranasal sinuses (HR, 5.00; 95% CI, 1.37-18.25) as independent risk factors. In the cohort of pts evaluated by central imaging review, involvement of the paranasal sinus was not significantly associated with CNS relapse. Conclusion: The involvement to adjacent sites/organs was risk of CNS relapse in pts with localized nasal ENKL who received non-anthracycline therapy. Our findings suggest that the pts with the involvement of the gingiva and/or palate need more effective treatment approaches to reduce CNS relapse. Disclosures Miyazaki: Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Sumitomo Group: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Astellas Pharma: Research Funding; Nippon Shinyaku: Research Funding; Shionogi Pharmaceutical: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Daiichi Sankyo: Research Funding; Toyama Chemical Co: Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin,: Honoraria, Research Funding; Chugai Pharma,: Honoraria, Research Funding. Suzuki:Kyowa-Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Mochida Pharmaceutical: Honoraria; Novartis: Honoraria; Shionogi: Honoraria; Takeda Pharmaceuticals: Honoraria; Meiji Seika Pharma: Honoraria; MSD: Research Funding; Ohtsuka: Honoraria; Sawai Pharmaceutical: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy. Asano:Chugai Pharma: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Terui:Novartis pharma: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Celgene: Honoraria; Bristol myers Squib: Honoraria. Kobayashi:Pfizer: Research Funding; Ohtuka: Research Funding; Astellas: Research Funding. Yamaguchi:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Teijin Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; ERYTECH Pharma: Consultancy; Sumitomo Group: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Katayama:Bristol-Myers Squibb: Honoraria; Teijin Pharma: Research Funding; Mochida Pharmaceutical Co. Ltd.,: Research Funding; Toyama Chemical Co: Research Funding; Ono Pharmaceutical: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding; Astellas Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria; Shionogi Pharmaceutical: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Taisho Toyama Pharma: Honoraria; Sysmex: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Group: Honoraria, Research Funding.

Abstract: Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON. Patients and Methods The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively). Results In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P 〈 .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols. Conclusion We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.

Abstract: A new high-sensitivity giant magneto-resistance (GMR) sensor system was developed and applied to a magnetic field microscope for which a magneto-impedance (MI) sensor was used as a high-sensitivity magnetic probe. The GMR sensor system achieved a detectivity of 13 pT/√Hz at 100 Hz. The sensing limit and spatial resolution were examined compared with the MI sensor. A 100 Hz AC magnetic field from a patterned Cu line was imaged. The GMR sensor showed better spatial resolution than that of the MI sensor owing to its small sensor unit size. The sensing limit was the same for both the GMR sensor and the MI sensor. This limit is due to ambient magnetic field noise. The GMR sensor could reduce this noise by differential detection using two sensor units. These results suggest that the GMR sensor system has advantages for application to the magnetic field microscopes compared with the MI sensor.

Abstract: To elucidate the long‐term outcomes of non‐anthracycline‐containing therapies and central nervous system (CNS) events in patients with extranodal NK/T‐cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow‐up of 8.4 years, the 5‐year overall survival (OS) and progression‐free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy‐dexamethasone, etoposide, ifosfamide, and carboplatin (RT‐DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT‐DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI] , 8.60–343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78–30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L‐asparaginase, and etoposide (SMILE) chemotherapy as first‐line treatment. Patients who received SMILE as their first‐line treatment tended to have better OS than those who did not ( p  = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease‐free at the last follow‐up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8‐year follow‐up revealed the long‐term efficacy and safety of RT‐DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.