Infectious complications in adults undergoing intensive chemotherapy for acute myeloid leukemia in 2001-2005 using the Japan Adult Leukemia Study Group AML201 protocols.

PURPOSE: The Japan Adult Leukemia Study Group (JALSG) AML201 protocols are regimens for remission induction and consolidation chemotherapy of acute myeloid leukemia (AML) and have been widely accepted in Japan since 2001. Management of infectious complications during chemotherapy has a key role in the supportive care of AML patients. METHODS: By using case report forms collected in December 2001 and December 2005, we retrospectively analyzed the infectious complications in adult patients treated by using the JALSG AML201 protocols against AML (excluding promyelocytic leukemia). RESULTS: Of 980 patients, 80.2% experienced febrile neutropenia (FN), 8.3% bacteremia/fungemia, and 10.3% pulmonary infection at least once during remission-induction chemotherapy. Gram-positive bacteremia accounted for 65.1% of bacteremia/fungemia in 2001-2005, compared with 38.2% in 1987-1991 and 45.9% in 1992-1995. Of 750 patients, 81.9% experienced FN, 21.9% bacteremia/fungemia, and 9.1% pulmonary infection at least once during consolidation chemotherapy. During consolidation chemotherapy, bacteremia/fungemia and pulmonary infection were significantly more frequent in the high-dose cytarabine (HDAC) arm than in the conventional multiagent arm (25.9 vs. 17.9% and 12.7 vs. 7.7%, respectively). Invasive pulmonary aspergillosis accounted for 15.8% of pulmonary infections during remission induction and 19.7% during consolidation chemotherapy. CONCLUSIONS: Our data suggest that patterns of infectious complications have changed between 1987 and 2005, possibly because of chemoprophylaxis with oral fluoroquinolones and improved diagnosis of invasive pulmonary aspergillosis by serum antigen analysis.

Management of infection during chemotherapy for acute leukemia in Japan: a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group.

PURPOSE: We performed a nationwide questionnaire-based survey to evaluate the current clinical practices of infectious complications during chemotherapy for acute leukemia in Japan. METHODS: We e-mailed a questionnaire to member institutions of the Japan Adult Leukemia Study Group in September, 2013. The questionnaire consisted of 50 multiple-choice questions covering therapeutic environment, antimicrobial prophylaxis, screening test during neutropenia, empirical therapy for febrile neutropenia, and the use of granulocyte-colony stimulating factor. The results were compared to those of previous surveys conducted in 2001 and 2007, and also to the recommendations described in the guidelines. RESULTS: Usable responses were received from 141 out of 222 (63.5%) institutions. Chemotherapy for acute myeloid leukemia was performed in protective environment in 90% of the institutions, which increased compared to previous survey (76%). Fluoroquinolones and fluconazole were the most commonly used antimicrobial agents for antibacterial and antifungal prophylaxis, followed by sulfamethoxazole-trimethoprim and itraconazole, respectively. In empirical therapy for febrile neutropenia, monotherapy with ß-lactum antibiotics was the first-line therapy in most of the institutions. While empirical antifungal therapy was adopted for persistent fever in more than half of the institutions, preemptive/presumptive therapy was also used in approximately 40% of the institutions. Most of the clinicians were reluctant to use granulocyte-colony stimulating factor routinely in chemotherapy for acute myeloid leukemia. CONCLUSIONS: This study clarified the current clinical practices of infectious complications during chemotherapy for acute leukemia and would provide important information for the development of a suitable guideline in Japan.

Langerhans Cell Histiocytosis With Unusual Hexagonal Crystals in Addition to Usual Charcot-Leyden Crystals. Report of a Patient With Possible Process of Crystal Formation and Clinical Significance of a "Necrotic" Change.

Langerhans cell histiocytosis is a rare neoplastic disorder characterized by the proliferation of Langerhans cells and often accompanied by eosinophil infiltration. Charcot-Leyden crystals, composed of galectin 10, are occasionally observed in Langerhans cell histiocytosis; however, histological images are rarely reported. We herein present a patient with Langerhans cell histiocytosis with Charcot-Leyden crystals and hexagonal crystals by describing the histologic and immunohistochemical features of a lymph node. A unique distribution of Charcot-Leyden crystals and hexagonal crystals was observed in this patient, shedding light on their possible formation process of the latter. We discuss the biological significance of eosinophilic abscesses in Langerhans cell histiocytosis and propose that these crystals may be linked to extracellular trap-cell death (ETosis). This example challenges the conventional characterization of "necrosis" in Langerhans cell histiocytosis and underscores the importance of recognizing ETosis as a potential mechanism involved in the pathogenesis of Langerhans cell histiocytosis. Further studies are underway to validate significance of these findings in a larger cohort of Langerhans cell histiocytosis patients.

The demarcation between younger and older acute myeloid leukemia patients: a pooled analysis of 3 prospective studies.

BACKGROUND: Contemporary treatment protocols for adult acute myeloid leukemia (AML) are age-specific, and older patients are generally treated less intensively than younger patients. However, it remains uncertain whether older but fit patients with AML really need to have their treatment attenuated. METHODS: To evaluate the contribution of age to outcome for patients with AML receiving intensive chemotherapy, data were analyzed for 2276 patients aged less than 65 years who were treated uniformly, regardless of age, in 3 consecutive prospective studies conducted by the Japan Adult Leukemia Study Group. RESULTS: A substantial drop in overall survival (OS) between patients aged 40 to 49 years and 50 to 64 years led to a focus on 2 comparisons: 1) age < 50 versus ≥ 50 years; and 2) age 50 to 54 versus 55 to 59 versus 60 to 64 years. OS was significantly better for patients aged < 50 years than that for those aged ≥ 50 years (49.6% and 37.0% at 5 years; P < .001); older patients were more susceptible to relapse, but not to early death or nonrelapse mortality. The significant differences in OS between these 2 age groups were equally seen for patients with favorable, intermediate, and adverse cytogenetics (P < .001 each). Outcomes for those aged 50 to 54, 55 to 59, and 60 to 64 years were similar, with 5-year OS rates of 38.2%, 35.1%, and 38.0%, respectively (P = .934), and no differences in early death or nonrelapse mortality were observed among these age groups. CONCLUSIONS: These findings justify the use of intensive chemotherapy without dose attenuation toward older but fit patients with AML, at least up to the age of 64 years.

[Relationship between red blood cell transfusion volume and posttransfusional iron overload in hematological diseases].

We retrospectively investigated the status of transfusional iron overload at Kinki University Hospital. One hundred and sixty three patients received more than 10 red blood cell (RBC) units per year in 2009 and 2010. Myelodysplastic syndrome (37.4%) and aplastic anemia (11.0%) accounted for about 50% of the underlying diseases. At the time of receiving a total of 20 RBC units, 90.8% and 66.2% of the 65 patients evaluated had more than 500 and 1,000 ng/ml of serum ferritin, respectively. The frequency of organ dysfunction associated with iron overload was 56.9% of all the patients assessed, 37.8% of patients with serum ferritin levels of 500∼999 ng/ml, and 67.4% of patients with serum ferritin levels >1,000 ng/ml. Although the Japanese guidelines propose 40 units of RBC transfusion and/or a serum ferritin level of 1,000 ng/ml as a good point to start iron chelation therapy, our results suggest that iron overload and consequent organ dysfunction may occur earlier than this. Therefore, it may be necessary to start iron chelation therapy earlier than that suggested by the Japanese guidelines.

Collision Tumor Comprising Primary Malignant Lymphoma and Adenocarcinoma in the Ascending Colon.

We describe the case of a 78-year-old man with collision tumor from the primary malignant lymphoma and adenocarcinoma in the ascending colon. He suffered anemia from sigmoid colon cancer, and colonoscopy revealed early-stage colorectal cancer with a diameter of 20 mm in the cecum, the biopsy specimen showed moderately differentiated adenocarcinoma. Contrast-enhanced computed tomography (CT) revealed bowel wall thickening with contrast enhancement at the cecum; however, no lymph node and organ metastases were found. As above, we performed laparoscopic ileocecal resection with D3 lymph node dissection. The postoperative course was uneventful, and he was discharged from the hospital on postoperative day 11. Histopathological findings were moderately differentiated adenocarcinoma which invaded the muscularis propria and serosa from the submucosa, while the adjacent serosa showed a highly diffuse proliferation of atypical cells with an irregular nuclear-to-cytoplasmic ratio. Besides, immunohistochemical staining findings were diffuse large B-cell lymphoma, and diffuse large B-cell lymphoma was coexistent with moderately differentiated adenocarcinoma. We treated the patient with cyclophosphamide, doxorubicin, vincristine, and prednisolone in combination with rituximab (R-CHOP therapy) during 3 months postoperatively. When the 8 courses had been completed, postoperative positron emission tomography-CT (PET-CT) confirmed complete response, and the disease control has been doing well. Malignant lymphoma of the colorectal region is relative rare, and the occurrence of synchronous lymphoma and adenocarcinoma of the colon is also rare. Furthermore, collision tumor by these different entities is very unusual. We presented here such a case. The accurate clinical determination of the dominant tumor and a close follow-up is required for proper treatment in these cases.

Clinical efficacy of all-trans retinoic acid for treating adult T cell leukemia.

PURPOSE: We previously reported that all-trans retinoic acid (ATRA) inhibited growth in human T-cell leukemia virus type I (HTLV-I)-positive T-cell lines and in fresh cells from patients with adult T cell leukemia (ATL). Here, we confirmed the clinical effects of ATRA in 20 patients with ATL. MATERIALS AND METHODS: The 20 patients (n = 20) with a median age of 56 (range 35-73) years who were diagnosed with ATL received ATRA orally. RESULTS: The efficacy of treatment was as follows: no complete response (CR), a partial response (PR) in 40% of the patients, no change (NC) in 45% of the patients, and a progressive disease (PD) in 15% of the patients. In seven acute-type ATL patients, a PR was achieved in two (28.5%), NC was observed in two (28.5%), and a PD was observed in three (42.8%). In three lymphoma-type ATL patients, a PR (100%) was achieved. Among four chronic-type ATL patients, a PR was achieved in one (25%) and NC was observed in the remaining three (75%). In six smoldering-type ATL patients, a PR was achieved in two (33.3%) and NC was observed in four (66.6%). The major side effects were headache (n = 5), transient liver dysfunction (n = 2), hyperlipidemia (n = 2), and anorexia (n = 1). CONCLUSION: These results indicated that ATRA might be a useful agent for the safe treatment of ATL.

Synchronous Occurrence of Mycosis Fungoides, Diffuse Large B Cell Lymphoma and Acute Myeloid Leukemia.

Patients with mycosis fungoides (MF), the most common subtype of primary cutaneous T-cell lymphoma, have an increased risk of developing secondary malignancies. We herein report two rare cases of MF concurring with diffuse large B cell lymphoma (B lymphoid lineage) and acute myeloid leukemia (myeloid lineage) in two otherwise healthy elderly patients. Potential etiologic factors, including the impact of the therapy-associated inflammatory response on the development of secondary tumors in patients with MF, are discussed. Further clinical, experimental and genetic studies are needed to elucidate possible physiopathogenic associations among the three concurrent malignancies occurring in the cases presented here.

Extramedullary blast crisis derived from 2 different clones in the central nervous system and neck during complete cytogenetic remission of chronic myelogenous leukemia treated with imatinib mesylate.

We describe a patient with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed an extramedullary blast crisis in the central nervous system (CNS) and then a subcutaneous tumor of the neck during treatment with imatinib mesylate. Administered 400 mg of imatinib mesylate after the diagnosis of chronic-phase CML, the patient achieved a complete cytogenetic remission 4 months later. However, he developed a mixed myeloid/B-cell blast crisis with additional karyotype abnormalities only in the CNS during a complete cytogenetic remission in the bone marrow. Several doses of intrathecal chemotherapy and whole-brain irradiation were effective in treating the blast crisis in the CNS. After 7 months of complete cytogenetic remission, the patient experienced a subcutaneous tumor in the right neck. A biopsy of the tumor revealed a mixed myeloid/T-cell blast crisis. The cytogenetic analysis showed that the blast crisis clone in the neck tumor was different from that of the CNS. An increased dose of imatinib mesylate was ineffective in treating the neck tumor. Irradiation to the right neck was therefore undertaken. This case suggests that the development of a clone resistant to imatinib mesylate is not always detected in the bone marrow and that multiple Ph-positive clones have the potential to become transformed into a blast crisis.

HIV-negative Primary Bone Marrow Hodgkin Lymphoma Manifesting with a High Fever Associated with Hemophagocytosis as the Initial Symptom: A Case Report and Review of the Previous Literature.

A 68-year-old man was referred to our hospital due to a high fever and pancytopenia. Neither tumors nor infectious lesions were detected. Hemophagocytosis was observed on the bone marrow (BM) smear, although without abnormal cells. Prednisolone therapy was ineffective for the patient's high fever. Later on, we obtained the results of a BM biopsy indicating the presence of infiltration of atypical Reed-Sternberg cells, leading to a diagnosis of HIV-negative primary bone marrow Hodgkin lymphoma (PBMHL). However, the patient died of multiple organ failure before receiving chemotherapy. As the clinical course of PBMHL is rapid, physicians must keep in mind its possibility in similar cases.

Eosinophilic colitis in a patient with acute myeloid leukemia after allogeneic bone marrow transplantation.

Eosinophilic colitis is a rare inflammatory disease characterized by eosinophilic infiltration of the colon and peripheral blood eosinophilia. We report on a case of eosinophilic colitis in a 29-year-old woman with acute myeloid leukemia following allogeneic bone marrow transplantation from her HLA-identical sister. To our knowledge, eosinophilic colitis has rarely been reported in association with allogeneic bone marrow transplantation.

Mutant type glutathione S-transferase theta 1 gene homologue to mTOR in myelodysplastic syndrome: possible clinical application of rapamycin.

In this study, we observed the expression of the GSTT-1 gene in patients with myelodysplastic syndrome (MDS) at the messenger RNA level. Reverse transcription-polymerase chain reaction (RT-PCR) for GSTT-1 was performed with a pair of primers complementary to the 5' coding section and the 3' coding section of the GSTT-1 cDNA for amplifying the 623-bp band. Among 20 patients with MDS, 8 patients showed the expected 623-bp band on RT-PCR, and 12 patients showed a 500-bp band on RT-PCR, indicating that a 123-bp sequence was deleted as a mutant of the GSTT-1 gene. Furthermore, a BLAST DNA search showed that the deletion of a 123 bp sequence creates a sequence that is 63% homologous to human FKBP-rapamycin associated protein (FRAP); this protein has been termed a mammalian target of rapamycin (mTOR). We respectively transfected the wild type and the mutant type GSTT-1 gene in an expression vector to two cell lines (K562 and HL-60). The stable transformants for the wild type and the mutant type GSTT-1 genes were made by G418 selection. Interestingly, rapamycin could induce significant growth inhibition of the stable transformants for mutant type GSTT-1, which was indicative of apoptosis, but not that of those for wild type GSTT-1. These results suggest that rapamycin could be included in the therapeutic modality for the patients with MDS who have the mTOR sequences in GSTT-1 gene.

Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial.

PURPOSE: The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. PATIENTS AND METHODS: Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. RESULTS: A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. CONCLUSION: In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

Clinical importance of human herpes virus-8 and human immunodeficiency virus infection in primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma that usually develops in immunosuppressed patients infected with human herpes virus-8 (HHV-8) in conjunction with human immunodeficiency virus (HIV) infection. However, there are several reports of HHV-8-related HIV-negative cases and HHV-8-unrelated HIV-negative cases, mainly in immunodeficient and elderly patients. Here, we report one case of HHV-8-related HIV-negative PEL with gastric cancer (case 1) and one case of HHV-8-unrelated HIV-negative effusion-based lymphoma (case 2), both in elderly men. A 73-year-old man and a 79-year-old man were admitted because of lymphomatous effusions, and no mass was detectable in both cases. They were diagnosed as having malignant effusion lymphoma on the basis of cytological findings indicating atypical lymphoid cells and the expression of CD20 and CD79a. To detect evidence of HHV-8 infection in neoplastic cells, immunocytochemical staining for ORF73/ latent nuclear antigen-1 (LNA-1) was performed. The results revealed that case 1 was ORF73-positive, and case 2 was ORF73-negative. Rituximab-based chemotherapy (R-THPCOP: rituximab, pirarubicin, cyclophosphamide, vincristine, prednisolone) was administered to both patients and complete remission was achieved in both. Compared to most HIV-positive PEL cases, these two cases showed a good response to chemotherapy. In cases of PEL, we should focus on HHV-8 infection and HIV status for determining prognosis.

Interleukin-8 in the pathogenesis of primary central nervous system lymphoma in association with HIV infection.

The pathogenesis of acquired immunodeficiency syndrome-associated primary central nervous system lymphoma (AIDS-associated PCNSL) remains unclear. However, cell adhesion molecules have been reported to be strongly associated with PCNSL. In this study, we established Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) from HIV-positive patients (LCL(HIV)) and normal individuals (LCL(N)). The expression of CD18 antigen by LCL(HIV) was stronger than that by LCL(N). We performed a cell adhesion assay using ISO-HAS, which is the human hemangiosarcoma cell line and expresses intercellular adhesion molecule 1 (CD54). The binding rates of LCL(HIV) and ISO-HAS without stimulation were higher than those of LCL(N). Further, we demonstrated that azidothymidine or simvastatin inhibited the binding rates of LCL(HIV) and ISO-HAS more significantly than those of LCL(N). Further, the levels of interleukin (IL)-8, a CD18 inducer, were higher in LCL(HIV) than in LCL(N). We conclude that interaction between IL-8 and CD18 may be critical to AIDS-related PCNSL.

Sub-acute demyelinating polyradiculoneuropathy as an initial symptom of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS).

Here we report the first case of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), who initially presented with peripheral neuropathy. Nerve conduction, cerebral spinal fluid studies and his clinical course were compatible with sub-acute demyelinating polyradiculoneuropathy. In addition, left cervical lymph node swelling was observed on admission. Diagnosis of PTCL-NOS was made by the histological, immunohistochemical, and Southern blot analyses on the biopsy specimen from the enlarged lymph node. Combination chemotherapy composed of cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) was effective for polyneuropathy as well as for lymphoma. Several antibodies relating to paraneoplastic syndrome such as Ma1, Ma2, Amphiphysin, CV2, Ri, Yo and Hu were all negative. Because sural nerve biopsy performed prior to CHOP therapy revealed no infiltration of lymphoma cells, immune dysfunction mediated by some cytokine or unidentified autoantibody related to PTCL-NOS was thought to be involved in the polyradiculoneuropathy.

Analysis of bacteremia/fungemia and pneumonia accompanying acute myelogenous leukemia from 1987 to 2001 in the Japan Adult Leukemia Study Group.

We analyzed the incidence and prognosis of bacteremia/fungemia and pneumonia during remission induction therapy of a newly diagnosed acute myelogenous leukemia (AML) in the Japan Adult Leukemia Study Group treated with individual protocols of AML-87/-89 (1987-1991), AML-92 (1992-1995), AML-95 (1995-1997), and AML-97 (1997-2001). Bacteremia/fungemia was present in 251 of 2585 cases (9.7%); the causative microorganism was gram-positive bacteria (GPB) in 122 cases (49%), gram-negative bacteria (GNB) in 90 cases (36%), fungi (F) in 31 cases (12%), and polymicrobes (P) in 8 cases (3%). Particularly prevalent were Pseudomonas aeruginosa in 49 cases (20%), Staphylococcus epidermidis in 29 cases (12%), and Staphylococcus aureus in 25 cases (10%). With AML-87/-89, incidence of bacteremia/fungemia was 11.8% while it was 9.4% with AML-92, 8.7% with AML-95, and 9.2% with AML-97. The proportion of GPB, GNB, F, and P was 40, 41, 16, and 3% in AML-87/-89, 46, 40, 11, and 3% in AML-92, 48, 39, 11, and 2% in AML-95, and 59, 26, 11, and 4% in AML-97. The mortality rate by period was 26.5, 16.4, 14.0, and 6.8%, respectively. Pneumonia was found in 433 cases (16.8%); microbiological research covered 359 cases of AML-87/-89, AML-92, AML-97 and excluded AML-95 as there was no listing for the causative microorganism on questionnaires. Microbiologically documented pneumonia was found in 123 cases (34.3%), with GPB in 33 cases (27%), GNB in 28 cases (23%), F in 44 cases (36%), and P in 18 cases (15%); particularly prevalent were Aspergillus in 23 cases (19%), Staphylococcus aureus in 16 cases (13%), and Pseudomonas aeruginosa in 15 cases (12%). The incidence of pneumonia overall was 24.6% with AML-87/-89, 16.9% with AML-92, 13.9% with AML-95, and 12.9% with AML-97, with a mortality rate of 28.9, 33.3, 16.7, and 16.7%, respectively. Incidence of bacteremia/fungemia and pneumonia complicating AML has tended to decline in recent years, and mortality has also tended to improve.

Efficacy of rituximab monotherapy for an elderly hemodialysis patient with primary cardiac lymphoma.

We report a case of primary cardiac lymphoma (PCL) occurring in a 76-year-old man during maintenance hemodialysis. Chest computed tomography (CT) revealed a tumor with pericardial effusion in the left ventricular posterior wall. Cytological examination of the pericardial fluid revealed monotonous lymphoid cells positive for B-cell markers, and clonal immunoglobulin heavy chain gene rearrangement was detected, indicating B-cell lymphoma. Rituximab monotherapy was administered biweekly at the therapeutic level on hemodialysis. The follow-up chest CT showed tumor disappearance with pericardial fluid after two courses of therapy. Rituximab monotherapy was effective for an elderly hemodialysis patient with PCL.