Epidemiology of visceral mycoses in patients with acute leukemia and myelodysplastic syndrome: Analyzing the national autopsy database in Japan.

Visceral mycoses (VM) are a deadly common infection in patients with acute leukemia and myelodysplastic syndrome (MDS). We retrospectively analyzed the data from the centralized "Annual Report of Autopsy Cases in Japan" that archives the national autopsy cases since 1989. Among the total of 175,615 archived autopsy cases, 7183 cases (4.1%) were acute leukemia and MDS patients. While VM was only found in 7756 cases (4.4% in total cases), we found VM had a disproportionally high prevalence among acute leukemia and MDS patients: 1562 VM cases (21.7%) and nearly sixfold higher in prevalence. Aspergillus spp. was the most predominant causative agent (45.0%), and Candida spp. was the second (22.7%) among confirmed single pathogen involved cases. The prevalence of Candida spp. infection decreased about 50% due to the widely use of fluconazole prophylaxis, which may skew toward doubling of the Mucormycetes incidence compared to 30 years ago. Complicated fungal infection (> one pathogen) was 11.0% in acute leukemia and MDS in 2015. It was 14.7 times higher than in other populations. Among 937 patients who received allogeneic hematopoietic cell transplantation (HCT), the prevalence of VM was 28.3% and 23.3% with GVHD. Aspergillus spp. was less prevalent, but Candida spp. was more associated with GVHD. Its prevalence remains stable. Although Aspergillus spp. was the primary causative agent, non-albicans Candida spp. was increasing as a breakthrough infection especially in GVHD cases. Complicated pathogen cases were more common in acute leukemia and MDS.

Visceral Mycoses in Autopsied Cases in Japan from 1989 to 2013.

BACKGROUND AND METHODS: Our group has continuously studied the epidemiology of visceral mycoses (VM) among autopsy cases in Japan from 1989 to 2013. RESULTS: First, from a total of 11,149 autopsied cases, 571 (5.1%) cases of VM were observed in 2013. It was significantly higher than those of 2005 (p < 0.05) and earlier. Notably, incidence of cases with mucormycetes (Muc) in 2013 was higher than that of 1997 and earlier (p < 0.001), especially in leukemia cases. Muc cases also showed higher rate of "severe infection" compared with other cases (p < .0001). Emerging diseases were also observed. Severe fever with thrombocytopenia syndrome cases showed high incidence of VM as a complication. In addition, we observed cases with the rare mycoses caused by Phialopohra verrucosa and Rhodotorula spp. in our analysis. Moreover, the predominant fungal agent of central nervous system infections changed from Cryptococcus spp. to Aspergillus spp. in 2013. This may be considered a breakthrough infection. CONCLUSION: The prevalence of VM in 2013 became higher than those of 2005 (p < 0.05) and earlier, with a notable increase of incidence in cases with Muc. The occurrence of breakthrough VM and emerging mycoses deserve attention.

Epidemiology of Zygomycosis: Analysis of National Data from Pathological Autopsy Cases in Japan.

BACKGROUND AND METHODS: To identify recent trends in the frequency of zygomycosis in autopsy cases, we conducted epidemiological analysis every four years from 1989 to 2009 using national data reported in the "Annual of Pathological Autopsy Cases in Japan." RESULTS: 153,615 cases were autopsied, of which 6622 (4.3%) were found to have had mycosis. Among these, there were 243 cases (3.7%) of zygomycosis, which was the fourth most predominant causative agent of mycoses among the monopathogen mycoses. Of the complicated mycoses, zygomycosis accounted for 56 cases. A total of 299 cases with zygomycoses were observed. The frequency of zygomycosis appeared to be generally stable over the twenty-year period from 1989 to 2009, at around 4% of autopsy cases having mycosis. Younger patients tended to have severe and complicated infections that were characteristic of zygomycosis, compared with non-zygomycosis. The pulmonary and gastrointestinal (GI) systems were the most common foci in our analysis, reflecting the severity of zygomycosis in these sites. Hematological disease was the most frequent underlying disease, but there was a peak of neonatal infections in 2009, which was the first time that this was observed in our studies. CONCLUSION: These results of the epidemiological analysis of autopsy cases with mycosis demonstrate that clinicians should promptly recognize and treat zygomycosis.

Therapy-related Acute Myeloid Leukemia after the Long-term Administration of Low-dose Etoposide for Chronic-type Adult T-cell Leukemia-lymphoma: A Case Report and Literature Review.

A 61-year-old woman with chronic-type adult T-cell leukemia-lymphoma (ATL) had been taking low-dose oral etoposide for progressive lymphocytosis. After taking this for 3.5 years, she was diagnosed with therapy-related acute myeloid leukemia (t-AML), with a chromosomal translocation of t (6:11) (q27; q23). She thus received remission induction therapy, consolidation therapy, and allogeneic hematopoietic stem cell transplantation. Although both t-AML and ATL were in remissive states, she died of a therapy-related infection within 1 year. We reviewed 12 reported cases of AML complicating ATL to better characterize this unusual disease. We should therefore include t-AML in the differential diagnosis when administering low-dose etoposide for ATL over a long period of time.

Infectious diseases in solid organ transplant recipients: Analysis of autopsied cases in Japan.

BACKGROUND: With the improvements in immunosuppressive agents and graft survival, infections such as mycoses have become major complications after solid organ transplantation (SOT). METHODS: Our group has continuously updated an epidemiological database of visceral mycoses (VM) among autopsy cases in Japan since 1989. Data on infectious agents and clinical information were complied using similar procedures. RESULTS: Among the all autopsied cases studied, 356 undergone SOT. Of these, 214 (60.1%) suffered from one or more types of infections, including 51 (14.3%) with VM. Thus, the incidence of VM was higher in SOT recipients than in non-transplanted cases (P < 0.0001). Aspergillus spp. (Asp) was the most predominant agent and Candida spp. was second. Specifically, among SOT recipients, Asp was the most predominant in liver and lung transplant recipients. Among the 217 autopsied liver transplants cases, the incidence of VM was highest in those with fulminant hepatitis (FH, P = 0.01). The incidence of cytomegalovirus infection tended to be higher in cases with mycosis (P = 0.06). Multivariate logistic regression analysis identified FH (odds ratio, 3.61, 95% confidence interval 1.34-9.75; P = 0.03) as an independent risk factor for mycosis in liver transplant recipients. CONCLUSION: This epidemiological analysis of autopsied cases provides a strong incentive to intensify efforts to diagnose and treat post-SOT infectious diseases.

Intracranial hemorrhage and platelet transfusion after administration of anti-platelets agents: Fukushima Prefecture.

We conducted a case series study to assess intracerebral hemorrhage (ICH) in the context of anti-platelets agents (APAs) and platelet (PLT) transfusion in Fukushima Prefecture.This study included patients who were newly diagnosed with ICH between January 2008 and June 2014 in the neurosurgical hospitals of Fukushima Prefecture.　Four of ten neurosurgical hospitals responded to our questionnaire.　Of 287 ICH patients, 51 (20.6%) were on APA therapy, of whom PLT transfusion was given to only one persistently bleeding patient who was on dual anti-platelet therapy.　In a follow-up survey, 30 out of 51 ICH patients on APA therapy, average age 75 years, were analyzed, of whom 21 (70%) were male.　The predominant underlying disease was diabetes mellitus.　It is interesting to note that peripheral artery disease and aortic aneurysm were among the indications for APAs.　ICH was mainly observed supratentorially.　Hematoma enlargement was observed in 13 (44.8%) cases.　By day 7, 3 patients (10%) had died from complications of ICH.　In this study, we show that ICH during APA therapy matched what was observed in Kanagawa Prefecture.　Whether or not a national survey differs, we anticipate greater statistical validity and an opportunity to improve patient outcomes in Japan and around the world.

[Epidemiology of Visceral Mycoses in Autopsy Cases in 2011].

To identify recent trends in the frequency of mycoses in autopsy cases, we performed an epidemiological analysis using the data reported in the "Annual Report of Autopsy Cases in Japan" from 2011. 12,339 cases were autopsied, of which 608 (4.9 %) were found to have fungal infections. Of these, 411 cases (67.6 %) were male, the median age was 67, and 353 cases were severe (58.1 %). Aspergillus spp. was the most predominant causative agent among those infected with one pathogen. These data corroborate our previous data from reports in 2007 and 2009. For the first time since 1989, we observed a case of mycoses caused by Exophiala spp. with adult T cell leukemia and lymphoma. The types of underlying disease were also typical of that in our previous analysis in 2009. These included solid cancers in 124 cases (20.4 %), leukemia in 83 cases (13.7 %), bacterial infections such as pneumonia 69 cases (11.3 %) and malignant lymphoma in 66 cases (10.9 %). In 2011, the number of mycoses following solid organ transplantation totaled 12 cases and was the most numerous since 2005. A limitation of this study may be that the epidemiology of autopsied cases includes the more severe end of the fungal infection spectrum, and selection bias could not be ruled out. Nonetheless, this epidemiological analysis of autopsied cases with fungal infection provides a strong incentive to intensify and improve efforts in diagnosing and treating visceral mycosis.

Autologous blood transfusion for hemodialysis patients: A case report and review of clinical reports and therapeutic features.

CASE REPORT: We describe a hemodialysis (HD) patient who successfully underwent total hip arthroplasty with autologous blood transfusion (ABT). There were several problems with collecting ABT in this setting. DISCUSSION: A literature search for HD patients and ABT produced 8 articles describing 29 patients. Higher doses of erythropoietin stimulating agents were used to collect ABT than for a typical HD session. In 75% of the cases autologous blood was collected just after HD to collect better quality blood. The optimal clinical procedures for ABT in HD patients need to be clarified.

Impact of platelet transfusion on survival of patients with intracerebral hemorrhage after administration of anti-platelet agents at a tertiary emergency center.

This study examined the impact of platelet transfusion (PLT) on the survival of intracerebral hemorrhage (ICH) patients who had been administered anti-platelet agents (APA). This retrospective cohort analysis investigated 432 patients (259 men, 60%) who were newly diagnosed with ICH between January 2006 and June 2011 at the tertiary emergency center of Kitasato University Hospital. Median age on arrival was 67.0 years (range, 40-95 years). ICH was subcortical in 72 patients (16.7%), supratentorial in 233 (53.9%), and infratentorial in 133 (30.8%). PLT was performed in 16 patients (3.7%). Within 90 days after admission to the center, 178 patients (41.2%) had died due to ICH. Before the onset of ICH, 66 patients had been prescribed APA because of atherosclerotic diseases. Multivariate regression analysis indicated APA administration was an independent risk factor for death within 7 days (odds ratio, 5.12; P = 0.006) and within 90 days (hazard ratio, 1.87; P = 0.006) after arrival. Regarding the effect of a PLT in ICH patients with APA, no patient with PLT died. PLT had a survival benefit on patients with ICH, according to our analysis. Further prospective analysis is necessary to confirm the effects of PLT on survival in ICH with APA.

Peripheral blood progenitor cell collection by two programs for autologous and allogeneic transplantation.

BACKGROUND: In the Spectra apheresis instrument (Terumo BCT), both manual (Spectra-MNC) and automated (Spectra-Auto) programs have been widely used to collect peripheral blood progenitor cells (PBPCs). However, direct comparison of these programs remains extremely limited. STUDY DESIGN AND METHODS: We investigated 188 collections and products from autologous (patient) and allogeneic (donor) subjects and analyzed a subset of 89 allogeneic collections and products. Twenty-nine subjects who received apheresis for 2 consecutive days using both programs were also evaluated with a paired crossover comparison. RESULTS: The two programs processed similar volumes, but run time was longer with Spectra-Auto. Yield and efficiency of CD34+ cell collection were similar between these programs in the whole cohort, although white blood cell (WBC) and mononuclear cell (MNC) yields were higher with Spectra-MNC. In the allogeneic cohort, yield and efficiency of WBC collection were greater in Spectra-MNC. However, collected WBCs, MNCs, and CD34+ cells were similar between these programs in paired comparison. Regardless of program, preapheresis peripheral WBC, MNC, and CD34+ cell counts correlated with the number of cells collected. In contrast, preapheresis WBC counts in the whole cohort were negatively correlated with collection efficiencies of CD34+ cells in Spectra-MNC but not Spectra-Auto. The products collected using Spectra-MNC contained more contaminating platelets (PLTs) than Spectra-Auto, with a corresponding reduction in postdonation circulating PLTs. CONCLUSION: Spectra-MNC and Spectra-Auto showed distinct features that should be considered on a case-by-case basis. Similar investigations should be undertaken as new collection platforms are introduced.

Incidence and clinical significance of aberrant T-cell marker expression on diffuse large B-cell lymphoma cells.

INTRODUCTION: Aberrant expression of T-cell markers is occasionally observed in B-cell lymphomas. We conducted a retrospective study to establish its incidence and to determine its relationship with clinical features of patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We reviewed DLBCL patients diagnosed between January 2002 and April 2009. Patients fulfilled the following criteria: (1) age >18 years, (2) HIV negative, (3) B-cell lymphoma confirmed by restricted expression of surface immunoglobulin light chains by flow cytometry (FCM). Aberrant T-cell marker expression (ATCME) was defined as positivity for CD2, CD3, CD4, CD7, and/or CD8 on DLBCL cells by FCM. Phenotyping was also performed by immunohistochemistry (IHC). Patients were grouped according to positive or negative ATCME and their clinical features including survival were compared. RESULTS: Of 150 patients, 11 (7.3%) showed ATCME; CD2 and CD7 were most often expressed. ATCME was less often detected and the signal was weaker using IHC. There were no statistically significant differences in clinical features between the two groups. CONCLUSIONS: FCM may be useful to detect ATCME in a small amount of lymphoma cells. The mechanism responsible for ATCME, and whether it contributes in any way to the pathogenesis of B-cell neoplastic transformation, requires clarification.

Epidemiology of visceral mycoses in autopsy cases in Japan: the data from 1989 to 2009 in the Annual of Pathological Autopsy Cases in Japan.

To identify recent trends in the frequency of mycoses in autopsy cases, we analyzed, on a four-year basis, the 1989-2009 data in the Annual of Pathological Autopsy Cases in Japan. Of the 13,787 (9235 males) autopsies conducted in 2009, 4.5% (633/13,787) involved fungal infections and of the latter, 60.3% (368/633) were found to have severe clinical manifestations. Among the 610 (96.4%) cases involving a single etiologic angent, the predominant pathogens were Aspergillus (299 cases; 49%) and Candida (184 cases; 30.2%). However, it should be noted that the prevalence of severe aspergillosis and candidiasis has been decreasing. Although the frequency of cases involving zygomycetes seemed to be generally remaining stable from 1989-2009, we noted for the first time a peak in 2009 in such infections in patients less than one year old. Finally, deep-seated infections caused by unidentified fungi would appear to be decreasing over the time of the survey. Our finding, it is hoped, will encourage physicians to actively pursue viscerial fungal infections.

Association of CD20 levels with clinicopathological parameters and its prognostic significance for patients with DLBCL.

Diffuse large B-cell lymphomas (DLBCL) express CD20. CD20 expression is described as negative, weak, or normal as determined by flow cytometry (FCM) and is an important target for the treatment of DLBCL. However, the impact of CD20 levels at onset of the disease on patient prognosis has not been fully elucidated. We analyzed 174 DLBCL cases newly diagnosed between January 1998 and April 2010. The relationship of the association between CD20 levels and patients' backgrounds and prognoses was analyzed using the Kaplan-Meier method and Cox proportional hazard regression. Of the 174 patients, three cases (1.7%) were defined as CD20 negative based on immunohistochemistry (IHC). Although the other 171 cases were positive by IHC, eight cases (4.7%) were defined as negative and 33 cases (19.3%) were defined as weak when analyzed by FCM. Of the 105 patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy, those who were CD20 negative (FCM) showed significantly inferior overall (hazard ratios (HR): 6.79, 95% CI: 1.32-34.96, p = 0.04) and progression-free survival (HR: 7.3, 95% CI: 1.49-35.8, p = 0.04) compared to patients who were CD20 normal. Our findings indicate that the CD20 level (FCM) at onset is an independent predictor of the prognosis of patients with DLBCL.

A patient with acute lymphoblastic leukaemia presenting with an extremely high level (21.0%) of HbA(1c).

A 52-year-old Japanese woman was referred to our hospital because of fever and coxalgia. She had a white blood cell count of 241 × 10(2)/µL with 59.6% blasts, which had a high nuclear/cytoplasmic ratio and variably condensed nuclear chromatin. Flow cytometry and chromosomal analysis of bone marrow cells indicated positive findings of CD10, CD19, CD34, HLA-DR antigens and t(9; 22)(q34; q11.2), respectively. No rearrangements of bcr/abl in peripheral blood neutrophils were found by fluorescence in situ hybridization, suggesting that she had B-acute lymphoblastic leukaemia with Ph chromosome. Blood glucose and HbA(1c) (glycated haemoglobin) levels on admission were 23.4 mmol/L and 21.0%, respectively. The results of 1.5 anhydro-d-glucitol and glycoalbumin tests revealed that she certainly had diabetes mellitus (DM). Insulin therapy was initiated. Her high level of HbA(1c) also suggested the possibility that the patient suffered from haemoglobinopathies in addition to DM. Sequencing analyses of α1-, α2- and ß-globin genes were all normal. The patient achieved complete remission (CR) by one month after her first course of chemotherapy, and the HbA(1c) level decreased to 10.4% following insulin therapy and chemotherapy, which were initiated when she attained CR. Her extremely high HbA(1c) level was due mainly to DM. Also, suppression of erythropoiesis by proliferation of leukaemic cells and latent iron deficiency might have partially contributed to the increased HbA(1c). This could result in a transient but extremely high HbA(1c) level. To our knowledge, this is the first report of an acute leukaemia patient who expressed an extremely high level of HbA(1c).

CD3- and CD4-positive plasmablastic lymphoma: a literature review of Japanese plasmablastic lymphoma cases.

Plasmablastic lymphoma (PBL) is a very rare and recently-described subtype of diffuse large B-cell lymphoma. A maxillary tumor in an 84-year-old HIV-negative Japanese-man was referred. The biopsied specimen showed a diffuse proliferation of mature plasma cells, expressing CD3 (+), CD4 (+), CD20 (-), CD138 (+) and EBER (+) by immunohistochemistry. He was diagnosed as a plasmablastic lymphoma; radiation therapy (RT) was started, but the response to the RT was only a partial response. To our knowledge, this is the first report of a patient with PBL expressing CD3 and CD4.

A case of giardiasis expressing severe systemic symptoms and marked hypereosinophilia.

An 88-year-old Japanese woman was referred to our hospital due to a one-month history of face edema, aphagia, shortness of breath, and skin rush over almost her entire skin. She had no abdominal symptoms. Her peripheral blood count showed a white blood cell (WBC) count of 27.1x10(9)/L with 82.1% eosinophils. Serum non-specific Immunoglobulin E was within a normal range. Soluble interleukin-2 receptor was elevated to 4200U/mL. At first, her eosinophil count was so high that we suspected she had an eosinophilic leukemia or hypereosinophilic syndrome. After admission, cysts of Giardia duodenalis (G. duodenalis) were detected in the patient's feces by microscopic analysis, then she was diagnosed with giardiasis, and 750mg per day of metronidazole was administered for seven days. Her WBC count decreased to 6.0x10(9)/L with 10% eosinophils, and her systemic symptoms improved. At that time her serum IL-5 was within a normal range. A few months later, the patient again complained of skin rush, and G. duodenalis was once again found in her feces. Her serum IL-5 was elevated to 751pg/mL. Metronidazole was administered for two weeks, and her eosinophil count decreased. G. duodenalis is a protozoan parasite, and it is one of the most common waterborne transmission gastrointestinal parasites in the world. G. duodenalis rarely causes hypereosinophilia. To our knowledge, this is the first case report of giardiasis with extreme hypereosinophilia and severe systemic symptoms.

CD20-positive T-cell large granular lymphocyte leukemia: case report and review of the literature.

CD20-positive T-cell malignancy is a rare disease. We report a case of CD20-positive T-cell large granular lymphocyte leukemia (T-LGLL). The leukemic cells were positive for CD20 and T cell markers, such as CD3, CD4, CD5, CD8 and CD57. A monoclonal rearrangement of the T-cell receptor (TCR) beta chain gene was detected. Twenty-three cases of well-documented CD20-positive T-cell malignancies were reviewed. Most cases were mature T-cell malignancies, especially exhibiting a cytotoxic T-cell phenotype, despite a diversity of the pathological diagnoses. Additional cases must be evaluated to clarify the implications of CD20 expression on T-cell malignancies and to elucidate whether such cases constitute a distinct biologic and clinical disease entity. The accumulation of cases will help to facilitate provision of a proper treatment for CD20-positive T-cell malignancies in the future.

Lymphoproliferative disorders after immunosuppressive therapy for aplastic anemia: a case report and literature review.

A 61-year-old Japanese man was referred to our hospital in 2002 due to severe pancytopenia. Bone marrow and peripheral blood findings indicated he had severe aplastic anemia (AA). A whole-body CT scan and Ga scintigraphy revealed no abnormal findings. Antithymocyte globulin and cyclosporine A (CyA) were administered and he got transfusion independently. In September 2004, he complained of abdominal fullness and a skin eruption in the lower abdomen. An abdominal CT revealed a spleen mass and lymphoadenopathy of the pancreas head. Splenectomy was done, and he was diagnosed with a diffuse large B cell lymphoma (DLBCL) of the spleen and skin. His karyotype was associated with t(14; 18). CyA was stopped, all lesions disappeared, and then his AA relapsed. In January 2007, antithymocyte globulin/CyA was readministered. In May 2007, he complained of acute swelling in his right thigh. A biopsy from the tumor revealed DLBCL. CyA was stopped again, yet the lymphoma did not regress. He was given R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone), followed by 5 cycles of R-VP (rituximab, vincristine, prednisolone) and radiation therapy, resulting in a partial remission. We report DLBCL after immunosuppressive therapy for AA. Although this is a rare complication, it should be considered before beginning immunosuppressive therapy.

Splenic infarction after Epstein-Barr virus infection in a patient with hereditary spherocytosis.

We describe the first patient with hereditary spherocytosis (HS) known to have developed splenic infarction following infectious mononucleosis (IM). An 18-year-old Japanese man was referred to our hospital in November 2004 because of continuous fever and icterus. He had undergone cholecystectomy at the age of 14 years. On patient admission in November 2004, a physical examination showed marked hepatosplenomegaly, icterus, and jaundice. He had a white blood cell count of 14.9 x 10(9)/L with 9.5% atypical lymphocytes, a red blood cell count of 2.93 x 10(12)/L, and a hemoglobin concentration of 7.8 g/dL. Microspherocytes were observed in the patient's peripheral blood smear, and immunoglobulin M antibody to Epstein-Barr virus (EBV) viral capsid antigen was detected. The patient's diagnosis was HS with IM. On day 4 of admission, the patient complained of severe abdominal pain. Abdominal computed tomography scanning revealed findings of splenic infarction. Two months after the occurrence of splenic infarction, a splenectomy was performed. A pathohistologic examination of the resected spleen revealed no evidence of thrombosis or arterial occlusion. We assume that the cause of splenic infarction was insufficient blood flow to oxygenate the entire spleen during the acute enlargement of the spleen.

[Early blastic transformation within a year of imatinib treatment in 2 cases of chronic myeloid leukemia].

We report herein on two rare cases of newly diagnosed chronic myeloid leukemia, which developed early blastic transformation within a year of imatinib treatment. Case 1 is a 22-year-old Japanese female, who underwent gradual blastic transformation with the increase of a resistant clone, which cytogenetically evolved right after she reached complete hematologic remission. Case 2 is a 24-year-old Japanese male, who underwent sudden transformation after 8 months treatment with imatinib mesylate following complete cytogenetic response. Although a sudden blastic transformation is extremely rare, the occurrence of such events even among the low-risk, good responding patients highlights the need for continued, rigorous monitoring by sensitive analysis, such as quantitative PCR. In order to accomplish the early eradication of minimal residual disease, the therapeutic strategy for chronic myeloid leukemia has to be defined in the era of imatinib, considering the application of allogeneic stem cell transplantation, which is currently the only curative treatment.