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.
Voices of Nagasaki after 75 Years Tomonaga, Masao
Journal for peace and nuclear disarmament,
03/2021, Letnik:
4, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
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.
Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells ...from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL.
A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg.
Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.
KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.
A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This article presents analyses of ...radiation effects on leukemia, lymphoma and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose-response relationship and, to the extent the data allowed, to investigate variation in the excess risks with gender, attained age, exposure age and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a nonlinear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this nonlinearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence that the radiation-associated excess leukemia risks, especially for acute myeloid leukemia, had persisted throughout the follow-up period out to 55 years after the bombings. As in earlier analyses, there was a weak suggestion of a radiation dose response for non-Hodgkin lymphoma among men, with no indication of such an effect among women. There was no evidence of radiation-associated excess risks for either Hodgkin lymphoma or multiple myeloma.
KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, ...pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL).
Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design.
Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses.
KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.
Summary
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.
Our previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), ...doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL.
Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis.
A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm.
The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.
1 Kings College, London, United Kingdom
2 James P. Wilmot Cancer Center, Rochester, New York, USA
3 Université de Rennes, Rennes, France
4 St. Marys Hospital Campus of Imperial College, London, ...United Kingdom
5 Institute of Pathology, Medical Hospital, Bayreuth, Germany
6 University of Minnesota, Minneapolis, Minnesota, USA
7 University of Pavia and Fondazione IRCCS Policlinico San Matteo, Italy
8 Université Paris XIII, Bobigny, France
9 University Dusseldorf, Dusseldorf, Germany
10 Karolinska Institute, Stockholm, Sweden
11 Saitama Medical University, Saitama, Japan
12 St Lukes International Hospital, Chuo-ku, Japan
13 Saitama Medical University, Saitama, Japan
14 University of Freiburg, Freiburg, Germany
15 Hospital Universitario La Fe, Valencia, Spain
16 Nagasaki University School of Medicine, Nagasaki, Japan
17 Hospital Universitario Vall dHebron, Barcelona, Spain and
18 University of Freiburg, Freiburg, Germany
Correspondence: Ghulam Mufti, Department of Haematology, Kings College Hospital, Denmark Hill, London, SE5 9RS United Kingdom. E.mail: ghulam.mufti{at}kcl.ac.uk
ABSTRACT
The classification of myelodysplastic syndromes is based on the morphological criteria proposed by the French-American-British (FAB) and World Health Organization (WHO) groups. Accurate enumeration of blast cells, although essential for diagnosis of myelodysplastic syndrome and for assignment to prognostic groups, is often difficult, due to imprecise criteria for the morphological definition of blasts and promyelocytes. An International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) of hematopathologists and hematologists expert in the field of myelodysplastic syndrome reviewed the morphological features of bone marrows from all subtypes of myelodysplastic syndrome and agreed on a set of recommendations, including recommendations for the definition and enumeration of blast cells and ring sideroblasts. It is recommended that (1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference. Clear definitions and a differential count of a sufficient number of cells is likely to improve precision in the diagnosis and classification of myelodysplastic syndrome. Recommendations should be applied in the context of the WHO classification.
Key words: myelodysplastic syndrome, myelodysplastic syndrome, myeloblast, ring sideroblast.
The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb ...survivors.
We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk.
There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young.
A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.
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