Soon after the second atomic bombing in 1945, hibakusha in Nagasaki saw the dawn of the Cold War, along with the Soviet Union’s possession of atomic bombs. The Cuban Missile Crisis in 1962 created a real fear of nuclear war capable of destroying all of humanity. The Partial Test Ban Treaty in 1963 and the Nuclear Nonproliferation Treaty (NPT) in 1968 were a good sign of hope. The Intermediate-Range Nuclear Forces Treaty, signed in 1987, also succeeded in reducing nuclear warheads in the 1990s. However, we have also seen nuclear deterrence strategies of the nuclear powers firmly established. The Cold War ended in 1989, but its nuclear deterrence policies have persisted. Unfortunately, the NPT regime has gradually begun to weaken since 2010. Hibakusha and nongovernmental organizations such as the International Campaign to Abolish Nuclear Weapons have stood firmly in strong solidarity and in 2017, succeeded in establishing the Treaty on the Prohibition of Nuclear Weapons (TPNW), which entered into force on 22 January 2021. Even now, hibakusha continue to suffer lifelong radiation-induced cancers and leukemia. Hibakusha must face a new stage in the abolition of nuclear weapons under a dangerous divide between NPT supporters and TPNW promoters. To overcome this divide, we need to increase the power of civil society around the world.

In October–November 2020, RECNA-Nagasaki University and Asia-Pacific Leadership Network (APLN) with the support of Nautilus Institute convened the Nagasaki 75th Anniversary scenario workshop to address the pandemic-nuclear nexus. About fifty participants of diverse background explored the future of nuclear war and nuclear disarmament in light of the uncertainty created by the global coronavirus pandemic. Their specific task was to develop four scenarios to identify the opportunities driven by global pandemics for Northeast Asian governments, civil society and market actors to reduce nuclear risk and resume nuclear disarmament. Based on these scenarios, the workshop recommended sixteen urgent steps that could be implemented globally and in particular, in Northeast Asia. With three more policy measures added after the workshop, this article elaborates nineteen policy recommendations.

Morphological features of eosinophils in patients with reactive eosinophilia (28 patients) and clonal eosinophilia (26 patients) have been compared with each other and with the eosinophil characteristics of healthy volunteers (three subjects) and of patients with the idiopathic hypereosinophilic syndrome (three patients). Morphological features, assessed in isolation from other haematological abnormalities, were found to have poor specificity for a myeloid neoplasm. The most useful feature was the presence of basophilic granules in mature eosinophils, which was associated particularly with acute myeloid leukaemia with inv(16). Marked reduction in granules occurred more often in some subsets of the myeloid neoplasm group but nevertheless was lacking in specificity since it was not infrequently seen in reactive eosinophilia. Although experienced morphologists more often considered that a myeloid neoplasm was likely in patients in whom this was the diagnosis (69%), myeloid neoplasia was also considered likely in a considerable proportion (39%) of patients with reactive eosinophilia. Morphological abnormalities of eosinophils therefore cannot be assessed in isolation in seeking to make a diagnosis of a myeloid neoplasm. Morphology is, however, needed and should be integrated with the results of other investigations.

Seventy-four years have passed since the atomic bombings of Hiroshima and Nagasaki. Approximately 210,000 victims died, and another 210,000 people survived. The damage to their health has continued, consisting of three phases of late effects: the appearance of leukemia, the first malignant disease, in 1949; an intermediate phase entailing the development of many types of cancer; and a final phase of lifelong cancers for hibakusha who experienced the bombing as a child, as well as a second wave of leukemia for elderly hibakusha and psychological damage such as depression and post-traumatic stress disorder. Thus, the human consequences of the atomic bombings have not ceased; many people are still dying of radiation-induced malignant diseases. Therefore, it is too early to finalize the total death toll. Hibakusha have faced a never-ending struggle to regenerate their lives and families under the fear of disease. As the only group of Homo sapiens experiencing real nuclear attacks, hibakusha have continued to engage in a lifelong movement to eliminate nuclear weapons. Political leaders, especially of nuclear-weapon states, must learn the wisdom of the hibakusha to save Homo sapiens from possible global extinction by nuclear war.

PURPOSE:Cancer risks for Nagasaki survivors once appeared to be lower than for Hiroshima survivors. The possibility that this was due to overestimation of the doses for the Nagasaki survivors was tested by measuring biological doses of Nagasaki survivors and comparing them with DS02R1 individual doses as previously done for Hiroshima survivors.MATERIALS AND METHODS:The electron spin resonance (ESR) method and cytogenetic method were used to estimate radiation doses for 24 Nagasaki survivors, and the results were compared to calculated DS02R1 doses.RESULTS:Six factory workers and 10 other survivors showed ESR or cytogenetically estimated doses that were in reasonably good agreement with their DS02R1 doses, while one factory worker was found to have an ESR dose estimate of nearly one half of the DS02R1 dose to the eye lens (a proxy organ for teeth). A few outliers were also observed.CONCLUSIONS:Although apparently lower cancer risks were observed in the past for Nagasaki survivors when compared to Hiroshima survivors, the present results do not indicate the existence of a trend that DS02R1 doses are overestimated when compared with biologically estimated tooth or cytogenetic doses. This observation is in line with the recent disappearance of the city difference in cancer risks.

An evaluation of the significance of specified dyserythropoietic features in suspected myelodysplastic syndrome (MDS) and acute myeloid leukaemia with erythroid dysplasia was made by means of evaluation of 100 electronic images of bone marrow erythroblasts from each of 20 subjects: 11 with a myeloid neoplasm, six with another condition that could cause erythroid dysplasia and three healthy controls. The evaluation was carried out independently by seven experienced haematologists/haematopathologists who were blinded to the diagnosis. The majority of the dyserythropoietic features listed in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues were validated, although karyorrhexis was found to be infrequent and lacking in specificity; multinuclearity and megaloblastosis were more often observed but also lacked specificity. Good majority agreement on the identification of dysplastic features was obtained. Despite this, it was demonstrated that a reliable diagnosis of MDS can often not be made on the basis of erythroid morphology alone. Interpretation of dyserythropoiesis must be carried out with full knowledge of other clinicopathological features and with a constant awareness of the other conditions that can be confused with MDS. An iron stain is essential, as cases with ring sideroblasts may otherwise not be recognised as having MDS.

On July 7 2017, the Treaty on the Prohibition of Nuclear Weapons (TPNW) was adopted by 122 non-nuclear-weapon states (NNWS). Japan, a NNWS in an extended deterrence relationship with the United Sta...

To fully understand the radiation effects of the atomic bombing of Hiroshima and Nagasaki among the survivors, radiation from neutron-induced radioisotopes in soil and other materials should be considered in addition to the initial radiation directly received from the bombs. This might be important for evaluating the radiation risks to the people who moved to these cities soon after the detonations and probably inhaled activated radioactive “dust.” Manganese-56 is known to be one of the dominant radioisotopes produced in soil by neutrons. Due to its short physical half-life, 56Mn emits residual radiation during the first hours after explosion. Hence, the biological effects of internal exposure of Wistar rats to 56Mn were investigated in the present study. MnO2 powder was activated by a neutron beam to produce radioactive 56Mn. Rats were divided into four groups: those exposed to 56Mn, to non-radioactive Mn, to 60Co γ rays (2 Gy, whole body), and those not exposed to any additional radiation (control). On days 3, 14, and 60 after exposure, the animals were killed and major organs were dissected and subjected to histopathological analysis. As described in more detail by an accompanying publication, the highest internal radiation dose was observed in the digestive system of the rats, followed by the lungs. It was found that the number of mitotic cells increased in the small intestine on day 3 after 56Mn and 60Co exposure, and this change persisted only in 56Mn-exposed animals. Lung tissue was severely damaged only by exposure to 56Mn, despite a rather low radiation dose (less than 0.1 Gy). These data suggest that internal exposure to 56Mn has a significant biological impact on the lungs and small intestine.

The percentage manifesting dysplasia in bone marrow needed to qualify as significant is ≥10 % in each lineage. However, detailed analyses of this threshold have not been reported. Here, we analyzed dyserythropoiesis (dysE) in 109 myelodysplastic syndromes (MDS) patients with 21 immune thrombocytopenia (ITP)/12 hemolytic anemia (HA) patients as a control. In present study, mild megaloblastic erythroblasts were specifically named ‘red cell with abnormal chromatin clumping (RCACC)’. RCACC ≥10 % in erythroblasts was observed in 29 % of ITP patients and 58 % of HA patients. The numbers of MDS patients with RCACC in erythroblasts <10, 10–19 and ≥20 % were 1, 3, and 105, respectively. We analyzed dysE criteria according to the WHO classification (original WHO dysE). Most of our MDS patients (98 %) had original WHO dysE ≥20 %. The ITP patients with original WHO dysE ≥10 % was 48 %, and there were no ITP patients had original WHO dysE ≥20 %. Sixty-seven percent of HA patients had original WHO dysE ≥10 %, and three patients (25 %) had original WHO dysE ≥20 %. Raising the threshold of the original WHO dysE from 10 to 20 or 30 % may provide more suitable criteria. If RCACC is not included in dysE criteria, we think that ‘10 %’ is a suitable threshold for the determination of dyserythropoiesis.

Evaluation of megakaryocyte morphology is difficult but can be essential for the diagnosis of myelodysplastic syndromes (MDS) and other myeloid neoplasms. We agreed upon descriptions and provided images of megakaryoblasts and of normal and dysplastic megakaryocytes, which were used as a basis for assessing the concordance of expert morphologists in their recognition. We showed a high rate of concordance for the recognition of micromegakaryocytes and confirmed their strong association with hematologic neoplasia, including MDS. Concordance was also found to be good for the recognition of multinucleated megakaryocytes, which showed a significant association with MDS. However cytoplasmic abnormalities were found not to be useful in MDS recognition. The occurrence of appreciable numbers of nonlobulated and hypolobulated megakaryocytes in individuals without a myeloid neoplasm was confirmed. We demonstrated that subjects without a myeloid neoplasm can have some megakaryocytes that are assessed as 'dysplastic' or 'possibly dysplastic' and that to avoid over diagnosis of dysplasia, 'possibly dysplastic' forms should be excluded from the count of dysplastic cells. Our results demonstrate that the nature as well as the presence of megakaryocyte dysplasia is important in the diagnosis of MDS; although evaluation of 30 megakaryocytes is strongly recommended, it may be possible to recognize diagnostically important dysplasia when fewer megakaryocytes are present but highly diagnostic forms are seen.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

Objective Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms' tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias. Methods The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital. Results The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR. Conclusion WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR.

Exposure to ionizing radiation is a known environmental risk factor for a variety of cancers including hematological malignancies, such as leukemia, myelodysplastic syndromes, and multiple myeloma. Therefore, for Hiroshima and Nagasaki atomic bomb survivors (surviving victims who were exposed to ionizing radiation emitted from the nuclear weapons), several cancer-screening tests have been provided annually, with government support, to detect the early stage of malignancies. An M-protein screening test has been used to detect multiple myeloma at an early stage among atomic bomb survivors. In the screening process, a number of patients with monoclonal gammopathy of undetermined significance (MGUS), in addition to multiple myeloma, have been identified. In 2009 and 2011, we reported the age- and sex-specific prevalence of MGUS between 1988 and 2004 and the possible role of radiation exposure in the development of MGUS using the screening data of more than 1000 patients with MGUS among approximately 52,000 Nagasaki atomic bomb survivors. The findings included: (1) a significant lower overall prevalence (2.1%) than that observed in Caucasian or African-origin populations; (2) a significantly higher prevalence in men than in women; (3) an age-related increase in the prevalence; (4) a significantly higher prevalence in people exposed to higher radiation doses only among those exposed at age 20 years or younger; and (5) a lower frequency of immunoglobulin M MGUS in Japanese patients than in patients in Western countries. The large study of MGUS among Nagasaki atomic bomb survivors has provided important findings for the etiology of MGUS, including a possible role of radiation exposure on the cause of MGUS and an ethnicity-related difference in the characteristics of MGUS.

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.

PURPOSE:CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL).PATIENTS AND METHODS:Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS).RESULTS:A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations (± standard deviation) after the eighth infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable.CONCLUSION:Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted.

7116 Background: Myelodysplastic syndromes (MDS) may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures. High-dose radiation exposure (such as an atomic bomb) increases the risk of developing MDS. Azacitidine (AZA), a hypomethylating agent, is the mainstay of therapy in MDS in Japan. But there have no reports investigating the efficacy of AZA in atomic bomb survivors suffering from MDS. Methods: We retrospectively evaluated 33 pts diagnosed MDS between April 2011 and April 2013 at Nagasaki Genbaku Hospital. All patients, included 13 atomic bomb survivors, received AZA. The primary objective was to estimate overall survival rates (OS). Results: The Table summarizes baseline characteristics and response rates. There was no clear difference in the background excluding age (P=0.0258) between atomic bomb survivors (A) and non-atomic bombed (non-A) pts. ORR (CR/mCR/PR) was no difference (P=0.2635), but the median OS at November 2013 was significantly different between two groups (13 months for A vs undefined for non-A, P=0.0429). Conclusions: These data demonstrated that despite the same ORR, OS of MDS pts in Nagasaki atomic bomb survivors was significantly short compared to non-atomic bombed pts. A certain influence by exposure of the atomic bomb can be considered. Further studies to clarify the cause are warranted. Atomic bomb survivor (A) n=13 Non-atomic bomb patients (non-A) n=20 P value Age (median) 68~84 (74) 46~87 (67) WHO subtype RCMD RAEB-1 RAEB-2 7 (54%) 2 (15%) 4 (31%) 13 (65%) 5 (25%) 7 (54%) 0.00258 IPSS at diagnosis Int-1 Int-2 High 5 (39%) 6 (46%) 2 (15%) 8 (40%) 10 (50%) 2 (10%) 0.2857 Cytogenetics Good Intermediate Poor 7 (54%) 3 (23%) 3 (23%) 8 (40%) 2 (10%) 10 (50%) 0.3020 Blood transfusion dependence + - 10 (77%) 3 (23%) 16 (80%) 4 (20%) 1.0000 Overall response rate CR marrow CR PR SD 2 (15%) 1 (8%) 2 (15%) 8 (62%) 7 (35%) 1 (5%) 0 (0%) 12 (60%) 0.2635 AZA cycle (median) 4 (1-19) 7 (1-21+)

Studies of morphology of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) refer to the definitions produced by the French-American-British (FAB) group and by the World Health Organization expert group. To clarify some points regarding the dysgranulopoiesis that are still unclear we analyzed a series of 98 neutrophils from MDS patients with regard to granularity, nuclear segmentation, the appearance of the chromatin, the presence of giant neutrophils, and the presence of nuclear chromatin extensions. We found that cells with at least 2/3 reduction of the content of granules, Pelger-like neutrophils, dysplastic non-Pelger cells, neutrophils with abnormal clumping of the chromatin, and macropolycytes could be recognized as dysplastic and included in the 10% count recommended by these two classifications. In addition, we suggest that neutrophils with more than 4 nuclear projections could be recognized as a relevant dysplastic feature.

Background: Mogamulizumab is a defucosylated humanized anti-CCR4 antibody with potent ADCC activity, and has been approved for the treatment of relapsed/refractory CCR4-positive adult T-cell leukemia-lymphoma in Japan. Based upon the results of a phase I study in Japan (J Clin Oncol 2010;28:1591) and a phase I/IIa study in the USA (ASH 2012), we evaluated the efficacy and safety of mogamulizumab in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).Methods: A multicenter phase II study in pts with relapsed CCR4-positive PTCL or CTCL who had received chemotherapy was conducted in Japan. The primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Pts received 1.0 mg/kg mogamulizumab intravenously once a week for 8 weeks. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee.Results: A total of 38 pts were enrolled, and 37 pts {29 PTCL and 8 CTCL; 23 male (62%); median age 64 (range 33-80) years; median number of prior systemic chemotherapy regimens 2 (range 1-6)} received mogamulizumab. Of the 37 pts, 25 completed the scheduled 8 infusions. Nine pts discontinued because of progressive disease and 3 because of adverse events (AEs). ORR was 35% (13/37, 95% CI, 20 to 53), with complete response rate of 14% (5/37). In subgroup analysis, ORR in pts with PTCL and CTCL was 34% and 38%, respectively. Median PFS of all 37 treated pts was 3.0 months (95% CI, 1.6 to 4.9), and median OS has not yet been reached. The most frequent grade 3/4 treatment-related AEs (TRAEs) were lymphopenia (73%), neutropenia (19%), leukopenia (14%) and skin disorders (11%). There was no treatment-related death or serious skin disorder like Stevens-Johnson syndrome. Infusion-related toxicity occurred in 24%, all of which was grade 2 or lower. Fifteen severe TRAEs were observed in 8 pts, including grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2, all of which improved.Conclusions: Mogamulizumab showed promising antitumor activity with an acceptable toxicity profile in pts with relapsed PTCL or CTCL, warranting further investigation. Background: Mogamulizumab is a defucosylated humanized anti-CCR4 antibody with potent ADCC activity, and has been approved for the treatment of relapsed/refractory CCR4-positive adult T-cell leukemia-lymphoma in Japan. Based upon the results of a phase I study in Japan (J Clin Oncol 2010;28:1591) and a phase I/IIa study in the USA (ASH 2012), we evaluated the efficacy and safety of mogamulizumab in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Methods: A multicenter phase II study in pts with relapsed CCR4-positive PTCL or CTCL who had received chemotherapy was conducted in Japan. The primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Pts received 1.0 mg/kg mogamulizumab intravenously once a week for 8 weeks. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee. Results: A total of 38 pts were enrolled, and 37 pts {29 PTCL and 8 CTCL; 23 male (62%); median age 64 (range 33-80) years; median number of prior systemic chemotherapy regimens 2 (range 1-6)} received mogamulizumab. Of the 37 pts, 25 completed the scheduled 8 infusions. Nine pts discontinued because of progressive disease and 3 because of adverse events (AEs). ORR was 35% (13/37, 95% CI, 20 to 53), with complete response rate of 14% (5/37). In subgroup analysis, ORR in pts with PTCL and CTCL was 34% and 38%, respectively. Median PFS of all 37 treated pts was 3.0 months (95% CI, 1.6 to 4.9), and median OS has not yet been reached. The most frequent grade 3/4 treatment-related AEs (TRAEs) were lymphopenia (73%), neutropenia (19%), leukopenia (14%) and skin disorders (11%). There was no treatment-related death or serious skin disorder like Stevens-Johnson syndrome. Infusion-related toxicity occurred in 24%, all of which was grade 2 or lower. Fifteen severe TRAEs were observed in 8 pts, including grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2, all of which improved. Conclusions: Mogamulizumab showed promising antitumor activity with an acceptable toxicity profile in pts with relapsed PTCL or CTCL, warranting further investigation.