Evaluation of a Treatment Algorithm for Tsushima Mamushi (Gloydius tsushimaensis) Snakebites, after Its Introduction to Tsushima Island, Nagasaki, Japan.

Objective Tsushima mamushi (Gloydius tsushimaensis) is an endemic species of snake inhabiting only Tsushima Island, a remote Japanese island. We conducted a multicenter, retrospective study of G. tsushimaensis bites for the first time and developed a treatment algorithm that unified treatment on the island and is still in use today. Methods This is a multicenter, retrospective study comparing 72 cases from January 2005 to December 2018, before the introduction of the algorithm, and 12 cases from January 2019 to December 2020, after its introduction. Results There was no significant decrease in the maximum grade of symptoms after the introduction of the algorithm, but there was a decreasing trend (p=0.057). Conversely, the median of the maximum creatinine kinase levels was 343.5 IU/L (interquartile range: 115.5-4,745.5) before the algorithm's introduction and significantly lower (142.5; interquartile range: 111.3-163) after the algorithm's introduction (p=0.042). After the algorithm's introduction, the disseminated intravascular coagulation merger rate and the acute kidney injury incidence both dropped to 0%, from 9.7% and 6.9%, respectively, before the algorithm's introduction. There was no significant difference in the length of hospital stay before versus after the algorithm's introduction. Conclusion This study showed that the treatment algorithm can be safely and quickly applied. The algorithm's effectiveness is expected to be strengthened by the accumulation of more cases in the future.

Severe hypofibrinogenemia in patients bitten by Gloydius tsushimaensis in Tsushima Island, Nagasaki, Japan, and treatment strategy.

Gloydius tsushimaensis is an endemic species inhabiting only Tsushima, a remote Japanese island, and is a distinct species from Gloydius blomhoffii widely distributed throughout mainland Japan and Gloydius brevicaudus and Gloydius ussuriensis which are geographically distributed in South Korea. This is the first multicenter retrospective study of G. tsushimaensis bites in Japan. A study of seventy-two patients who visited the former Izuhara Hospital, the former Naka Tsushima Hospital, Tsushima Hospital, and Kamitsushima Hospital during the fourteen years from January 1, 2005, to December 31, 2018, revealed the typical clinical characteristics of G. tsushimaensis bites. Five out of seventy-two cases (6.9%) showed severe hypofibrinogenemia, in which fibrinogen levels were below 100 mg/dl, which is an unreported clinical finding for G. blomhoffii bites. Generally, when fibrinogen levels are lower than 100 mg/dl, the bleeding risk increases, and it is perilous. Severe hypofibrinogenemia cases did not improve after G. blomhoffii antivenom administration. Additionally, all five cases had disseminated intravascular coagulation, and there were two cases of acute kidney injury and one death. five cases had a median maximum creatine kinase level of 5171 IU/l (Interquartile range: 4992-41,310). Although the mechanism is not precise, coagulation tests showed that the G. tsushimaensis venom contains a thrombin-like enzyme. Based on this research, we created an algorithm for the treatment of G. tsushimaensis bites and unified the treatment methods used on the island.

Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long-term study of indolent adult T-cell leukemia-lymphoma.

The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group.

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.

Fatal Cytomegalovirus Pneumonia and Associated Herpes Virus Infection in a Relapsed/Refractory Multiple Myeloma Patient Treated with Bortezomib plus Dexamethasone.

Multiple myeloma (MM) remains a largely incurable disease in the long term despite positive responses to first-line chemotherapy. Herein we report the case of a 68-year-old woman who died following treatment with bortezomib plus dexamethasone for refractory MM. The combination was associated with significant antitumor activity, but bacterial pneumonia/sepsis was followed by bilateral cytomegalovirus pneumonia with herpes simplex co-infection, and this was almost certainly the cause of death. Physicians need to pay careful attention when treating patients with refractory MM with bortezomib plus dexamethasone, and to be mindful that antiviral therapy may be needed in some cases.

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma.

We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m(2), the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m(2)/day on days 1-4, vincristine 0.4 mg/m(2)/day on days 1-4, doxorubicin 10 mg/m(2)/day on days 1-4, cyclophosphamide 750 mg/m(2)/day on day 6, and prednisolone 60 mg/m(2)/day on days 1-6). Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.

Imatinib provides durable molecular and cytogenetic responses in a practical setting for both newly diagnosed and previously treated chronic myelogenous leukemia: a study in nagasaki prefecture, Japan.

To evaluate the efficacy of imatinib in a practical setting, we registered 43 patients with newly diagnosed chronic myelogenous leukemia (CML) (group I) and 56 patients with previously diagnosed CML (group II) at 11 hematology centers in Nagasaki prefecture, Japan, from December 2001 to July 2005 and analyzed the molecular responses. Cytopenia, fluid retention, and skin rash were major adverse events, along with elevation in creatine phosphokinase levels. With a follow-up of approximately 3.5 years, imatinib treatment led to 88.7% overall survival (OS) and 85.2% progression-free survival (PFS) rates for group I, and 79.8% OS and 76.6% PFS rates for group II; the rates were not significantly different despite a lower average imatinib dose in group II. The rates of complete cytogenetic response at 30 months and major molecular response at 24 months were 86.1% and 62.5%, respectively, in group I, and 77.9% and 58.3% in group II; the rates were not significantly different. As has been reported by other groups, these results demonstrate that imatinib treatment can provide excellent clinical and molecular effects for not only newly diagnosed but also previously treated CML patients in practical settings that cover a wider variety of patients than clinical trials.

Inactivation of p14ARF as a key event for the progression of adult T cell leukemia/lymphoma.

The INK4a/ARF locus encodes two different proteins, p16INK4a and p14ARF, which are crucial for two tumor suppressor pathways. We found that p14ARF mRNA expression was suppressed in 13 of 37 cases, among which 9 cases showed the inactivation of both of p14ARF and p16INK4a, and 4 cases showed the inactivation of p14ARF alone. The inactivation of p14ARF and the mutation of p53 are mutually exclusive. The patients with the p14ARF inactivation had shorter survival, similar to that of patients with the p53 mutation. These results indicate that the inactivation of p14ARF plays a key role in the progression of ATLL.

Impact of p53 aberration on the progression of Adult T-cell Leukemia/Lymphoma.

Based on statistical analysis of its age-dependent occurrence, a multi-step carcinogenesis model has been proposed for Adult T-cell Leukemia/Lymphoma (ATLL). We have previously reported that the deletion of the p16 gene is a key event in ATLL progression. In the current study, we report for the first time that the aberrations of p16 and p53 are mutually exclusive in ATLL and either of the two events is sufficient for the ATLL progression. More than half of the patients had one of the two aberrations, and both aberrations emerged as significant markers for a poor prognosis.

A case of mucosa-associated lymphoid tissue lymphoma of the ampulla of Vater: successful treatment with radiation therapy.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the papilla of Vater is rare, and little is known of either its association with Helicobacter pylori infection or the optimal treatment modalities. We describe the first case of MALT lymphoma involving the major papilla that remained unchanged despite eradication of H. pylori, but which regressed following radiotherapy. A 46-year-old asymptomatic man was admitted to hospital for treatment of MALT lymphoma involving the papilla of Vater. Duodenal endoscopy showed multiple granules around the major ampulla, and biopsies revealed mucosal proliferation of centrocyte-like cells, lymphoepithelial lesions, hyperplastic lymphoid follicles and plasmacytic differentiation. The lymphoma cells were positive for B-cell but negative for T-cell markers, and expressed Bcl-2 but showed no immunoreactivity for CD5, CD10 and cyclin D, consistent with MALT lymphoma. The patient was successfully treated with triple therapy of lansoprazole, amoxicillin and clarithromycin for 1 week for coexisting H. pylori infection in the stomach, but the lymphoma lesions remained unchanged. Then, involved-field irradiation was applied at a total dose of 30 Gy delivered in 1.5 Gy fractions without any adverse events. Six months later, repeat endoscopy revealed disappearance of the granular lesions and lack of lymphoma cells in biopsy specimens. Four years after the commencement of radiotherapy, the patient is still in complete remission. Radiotherapy seems a safe and effective treatment modality for low-grade MALT lymphoma of the ampulla of Vater.

Aberrant processing of Fas transcripts in adult T-cell leukemia: a possible role in tumor cell survival.

In adult T-cell leukemia (ATL), tumor cells commonly express abundant membrane-bound Fas antigen. We reported a significant correlation between Fas expression status of ATL patients and their clinical outcome. In the current study, we analyzed the Fas cDNA sequence of the distinctive ATL cases that barely expressed mFas identified during the previous study. According to the results, changes in the Fas amino acid sequence were deduced in two of seven cases. Furthermore, we identified seven novel variants of Fas mRNA produced by alternative splicing. Our data indicates the diversity of Fas gene expression at a mRNA level in ATL.

Multiple gammac-receptor expression in adult T-cell leukemia.

Constitutive expression of the IL-2 receptor (IL-2R) on adult T-cell leukemia (ATL) cells and the presence of permanent IL-2-dependent ATL cell lines indicate that the signal transduction system via IL-2R is a key element for the development of this disease. IL-2R is a member of the common gamma-chain (gammac)-receptor family and shares gamma with IL-4R, IL-7R, IL-9R, and IL-15R. In addition to IL-2R, ATL cells express IL-15R and respond to IL-15. In the present study, we examined other members of this receptor family. ATL cells showed various levels of IL-4Ralpha (CD124) and IL-7Ralpha (CD127) expression, and responded to these cytokines. In contrast, ATL cells hardly responded to IL-9. As primary samples were a mixed population and the results may have been modified by contaminating normal cells, we used ATL cell lines as pure ATL cell populations. Here, we report that IL-2-dependent ATL cell lines also express IL-4Ralpha and respond to IL-4, which was verified by the activation of cytoplasmic transcriptional activator Stat6 protein. Moreover, a novel ATL cell line that grows stably in an IL-7-dependent manner was established from one of the cell lines, and IL-7 induced Stat5 activation in this cell line. These results indicated that ATL cells have the potential to express all gammac-receptors except IL-9R. Overlapping and switching of cytokine receptors supported the idea that ATL cells can rapidly select the appropriate gammac-receptor according to conditions.

The conformational alteration of the mutated extracellular domain of Fas in an adult T cell leukemia cell line.

Fas (APO-1/CD95) is a cell surface receptor involved in apoptosis. Almost all adult T cell leukemia (ATL) cells express abundant Fas antigen and show apoptosis induced by IgM anti-Fas monoclonal antibody (mAb). We established the ATL cell line, RSO4, which was obtained from Fas-sensitive ATL cell line SO4 and showed resistance to apoptosis induced by the mAb. By sequencing analysis of Fas gene, we found the mutation with the transition of A-G at nucleotide 373 at exon 2 among the extracellular domain (ECD), resulting in substitution of arginine for histidine. The molecular modeling suggested the definitive conformational alteration around residues 52-58 among the cysteine-rich domain (CRD) 1. It was suggested that the polymerization of Fas antigen, which was the essential process for the efficient induction of apoptosis, was interfered by the alteration of CRD1, and that this portion, named the "histidine-rich region," played a critical role in Fas assembly.