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Introduction Invasive fungal infections have been attracting attention as significant fatal complications in patients with febrile neutropenia (FN) who undergo intensive chemotherapy or hematopoietic stem cell transplantation to treat hematological malignancies. Although clinical trials are already underway in other countries, evidence supporting the use of caspofungin (CAS) in FN patients in Japan is still insufficient. Methods A retrospective study of patients treated with CAS for FN associated with hematological diseases between April 2015 and March 2018 was conducted to determine the treatment efficacy and safety. The study was conducted as a multicenter collaboration, and the data of 52 patients who met all of the inclusion criteria were analyzed. A five-composite-endpoint method was used, and the treatment was judged to be effective when all five endpoints (defervescence during neutropenia; no breakthrough fungal infections; resolution of baseline fungal infections; a survival for seven days or more after the completion of therapy; and no discontinuation of therapy due to side effects or invalidity) were met. Results The efficacy rate was 53.8% (28/52), which is close to the average reported efficacy rate. Adverse events included liver dysfunction and electrolyte abnormalities, but no renal dysfunction or serious events were seen. Conclusion These results suggest that the use of CAS in FN patients with hematological diseases is effective and well-tolerated, and we believe that the use of CAS could become a significant treatment in Japan.

Primary testicular lymphoma (PTL) is a rare but aggressive disease. Although most patients present in the early stage, their prognosis is poor. Similar with PTL, cardiac lymphoma is also an uncommon disease characterized by its aggressive clinical course and poor prognosis. We herein report an extremely rare case of advanced stage PTL with cardiac involvement, treated by high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) followed by systemic chemotherapy, prophylactic intrathecal methotrexate (IT-MTX), and radiotherapy. A 48-year-old man presented with painless left scrotal swelling. He was diagnosed with PTL after orchiectomy, and the histological type was diffuse large B-cell lymphoma. For staging of lymphoma, positron emission tomography was performed, which revealed uptake in the right atrium and early cardiac metastasis within just 2 months after orchiectomy. He underwent 6 cycles of systemic chemotherapy that consisted of rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone (R-CHOP). He also received central nervous system prophylaxis 4 times with weekly IT-MTX during the first 2 cycles of R-CHOP. He achieved complete response after 6 cycles of R-CHOP, and underwent HDT-ASCT and radiotherapy as consolidation therapy without irreversible adverse effects. He is currently doing well, with a progression-free survival of 31 months. The above treatment strategy including HDT-ASCT may be one of the treatment options for advanced stage PTL with cardiac metastasis in patients younger than 65 years old.

Upshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation.Here, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls.Pathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p 0.05), while C5b-9 staining did not differ significantly among groups.These findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.

Paraneoplastic pemphigus (PNP) is a rare, fatal, paraneoplastic autoimmune mucocutaneous blistering disease, commonly associated with lymphoproliferative disorders, including malignant lymphomas. Lymphoproliferative disorders associated with PNP are sometimes associated with a serious lung complication, bronchiolitis obliterans (BO). Due to its rarity, guidelines for the management of PNP have not been established. Furthermore, most patients die within 1 year. Here we report the successful treatment of lymphoma-associated PNP and BO using R-CHOP chemotherapy. A 53-year-old Japanese man was admitted to our hospital for severe erosive stomatitis. Computed tomography and positron emission tomography showed multiple lymphadenopathies. He was diagnosed with follicular lymphoma (Ann Arbor stage IVA) and PNP-related BO. The patient underwent six cycles of R-CHOP and an additional cycle of rituximab. Both the erosive stomatitis and the obstructive lung disease persisted, but complete response of the follicular lymphoma was achieved. The patient survived 27 months after diagnosis. Although he died from progressive respiratory failure due to BO, we note that this patient achieved the longest survival of any reported case of PNP-related BO associated with a lymphoproliferative disorder. The present case suggests that intensive immunochemotherapy for underlying lymphoma may improve the prognosis in patients with PNP-related BO associated with lymphoma.

Purpose: To report the limited usefulness of polymerase chain reaction (PCR)-based immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement analysis in diagnosing primary ocular adnexal lymphomas (OAL) treated with corticosteroids before biopsy. Observations: This was a case series of two patients: a 47-year-old woman and a 43-year-old man, who both presented with impaired visual acuity and ophthalmoplegia of the involved eyes. Both patients had previously received non-diagnostic biopsy and had been subsequently treated with corticosteroids. The visual acuity and ophthalmoplegia progressively worsened after a variable duration of remission. Ocular magnetic resonance imaging revealed gadolinium-enhancing intra- and extraconal lesions. Systemic evaluations did not reveal any other lesions outside of the orbit. Differential diagnoses were lymphoproliferative disorders, including undiagnosed primary OALs, and idiopathic ocular inflammation. Both patients were exposed to repeated biopsies. The biopsied tissue demonstrated marked lymphocytolysis due to corticosteroid usage; therefore, histology and immunophenotype were non-diagnostic. EuroClonality/BIOMED-2 PCR-based gene rearrangement analyses detected genetic clonalities of Ig and TCR and suggested diagnoses of primary OALs of B-cell and T-cell origins, respectively. An OAL of B-cell origin was treated with radiotherapy; an OAL of a rare T-cell origin was treated with high-dose methotrexate-based chemotherapy and adjuvant radiotherapy. Both patients remained progression free for more than 36 months. Conclusions and importance: PCR-based gene rearrangement analysis can be of limited usefulness in suggesting a diagnosis of primary OAL in patients receiving pre-biopsy corticosteroid treatment. Identification of genetic clonality is of clinical importance to provide treatment options for undiagnosed OALs. Keywords: Ocular adnexal lymphomas, Corticosteroids, B-cell, T-cell, Polymerase chain reaction, Gene rearrangement, Immunoglobulin, T-cell receptor

The optical properties of (Y,Gd)2O3:Eu and Y2O3:Eu were examined under both UV and VUV excitation. The evaluation found that the optical properties were greatly different between VUV and UV excitation. Higher luminance and shorter afterglow were also confirmed in comparison with Y2O3:Eu. Additionally, the temperature dependence of the luminance was improved by Gd substitution.

Temperature management of refrigerators that keep blood components is extremely important in blood transfusion. In our hospital we introduced a computerized blood temperature management system (BTMS) to control the temperature of refrigerators 24 hours a day. When a temperature deviated from an appropriate range, people near the refrigerator were warned by a buzzer and an alarm light. Information about the event was then transmitted automatically by pager to a manager in real time. In one year (Apr. 2000-Mar. 2001), 71 temperature anomalies occurred. Delays in closing the refrigerator door were the most frequent anomalies (38 cases, 53.5%), and temperature recovery time averaged 181 seconds. Temperature data were recorded in a server computer. We concluded that BTMS was useful for ensuring the quality of blood components. This system would be effective for 24-hour refrigerator temperature management, even in center without a manager.

1-beta-D-Arabinofuranosylcytosine (ara-C) is used empirically at a low, conventional, or high dose. Ara-C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ara-C, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). However, ara-CTP has seldom been monitored during low- and conventional-dose ara-C therapies because detection methods were insufficiently sensitive. Here, with the use of our newly established method (Cancer Res., 56, 1800 -- 1804 (1996)), ara-CTP was monitored in leukemic cells from acute myelogenous leukemia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg / m(2) ) (3 patients), continuous ara-C infusion (20 or 70 mg / m(2) / 24 h) (7 patients), 2-h ara-C infusion (70 mg / m(2) ) (4 patients), and 2-h infusion of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine, a deaminase-resistant ara-C derivative (70 mg / m(2) ) (6 patients)]. Ara-CTP could be determined at levels under 1 microM. There was a close correlation between the elimination half-life values of the plasma ara-C and the intracellular ara-CTP. The presence of ara-C in the plasma was important to maintain ara-CTP. The continuous ara-C and the 2-h N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine infusions maintained ara-CTP and the plasma ara-C longer than the subcutaneous ara-C or the 2-h ara-C infusion. They also afforded relatively higher ara-CTP concentrations, and consequently produced ara-CTP more efficiently than the 2-h ara-C infusion. Different administration methods produced different quantities of ara-CTP even at the same dose.

A retrospective study was performed on 125 patients with de-novo acute myeloid leukemia (AML) who had received first remission induction therapy at Fukui Medical University Hospital in the 16 years between 1983 and 1998. For remission induction therapies, patients in the 1980s received mainly behenoylcytarabine (BHAC), 6-mercaptopurine (6-MP), and prednisolone (PSL), plus aclarubicin (ACR) or daunorubicin (DNR). Patients in the 1990s received mainly BHAC, 6-MP, and etoposide (VP-16) plus DNR or mitoxantrone (MIT) or idarubicin (IDA). Patients with hypoplastic bone marrow received low-dose cytarabine (Ara-C) therapy or cytarabine ocfosfate (SPAC). Since 1992, patients with French-American-British disease classification of M3 have received all-trans retinoic acid (ATRA) (+/-chemotherapy). In the 1990s, more intensified postremission therapy was performed compared with that done in the 1980s. The complete remission (CR) rate of all patients was 58%. Predicted 6-year overall survival (OS) and disease-free survival (DFS) rates in the CR patients were 22% and 28%, respectively. Multivariate analysis showed age and leukocyte counts as significant prognostic factors regarding CR, OS, and DFS rates. The CR and OS rates in the 1990s were improved significantly from those in the 1980s, at 69% versus 48% (P = 0.016), and 32% versus 15% (P = 0.0014), respectively. The early death rate, within 30 days, was decreased from 26% in the 1980s to 9% in the 1990s (P = 0.013). This decrease was thought to be the main cause of the high CR rate in the 1990s. However, DFS was not significantly improved. It is necessary to establish more effective postremission therapies in order to reduce the relapse rate and improve the prognosis.

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

This work was undertaken to determine baseline urate metabolism in patients during the intermittent phase of gouty arthritis in order to decide on the best treatment for hyperuricemia. Parameters affecting serum urate levels, including uric acid clearance and urinary urate excretion, were re-evaluated in 30 patients who had shown normouricemia and no gouty attacks for at least 1 year and who were receiving urate-lowering drugs. The parameters determined at 2 weeks after discontinuation of the treatment (re-evaluation) were compared with those determined at initial diagnosis (initial evaluation). The discontinuation of urate-lowering drugs at re-evaluation led to a hyperuricemic state in all patients. The serum urate levels at re-evaluation were significantly higher than those at initial evaluation. The mean quantity of urinary urate excretion in patients showing increases in serum urate levels and the number of patients classified with overproductive hyperuricemia increased at re-evaluation. There was a significant increase in γ-glutamyl transpeptidase level, but no changes in body weight or creatinine and uric acid clearance. Asymptomatic patients at intermittent phases of gout may be in a latent, but progressing, hyperuricemic state as a result of urate overproduction. Physicians should assess latent hyperuricemia periodically, and choose a treatment with xanthine oxidase inhibitor when necessary.

Inosine 5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting reaction of guanine nucleotide biosynthesis and has been implicated in the reaction of cell growth and differentiation. We investigated the ability of mycophenolate mofetil, a prodrug of mycophenolic acid, to induce differentiation in HL-60 and U937 leukemic cells as well as in fresh leukemia cells from patients with non-lymphocytic leukemia. Treatment with mycophenolate mofetil reduced the intracellular guanosine 5'-triphosphate (GTP) levels and induced morphologic and functional differentiation in HL-60 and U937 cells dose-dependently. HL-60 and U937 cells developed macrophage-like cytoplasm as well as the expression of CD11b and CD14 antigens and the ability to oxidize nitroblue tetrazorium (NBT). These changes became evident when the intracellular GTP levels decreased to approximately 20-30% of the untreated control level and were abrogated by the addition of guanosine. In the fresh leukemic cells, differentiation induction was shown in the cells derived from seven of 13 patients. The fresh leukemia cells responding to mycophenolate mofetil revealed significant higher positivity to CD11b, CD14, and NBT before treatment and significantly reduced intracellular GTP levels after treatment compared to the non-responding cells. These findings suggest that mycophenolate mofetil induces differentiation in HL-60 and U937 cells and some fresh leukemia cells with moderate tendency to maturation, by causing a decrease in the intracellular GTP levels. Mycophenolate mofetil could be a promising differentiation inducer in vivo.

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.

The prophylactic efficacy of ofloxacin (OFLX) therapy was evaluated in 51 granulocytopenic episodes in 22 patients with hematological malignancies during post-remission chemotherapy in a prospective, randomized, controlled trial. Oral administration of OFLX plus amphotericin-B (AMPH) and polymyxin-B (PL) reduced episodes of fever and infection more than did the control regimen with PL and AMPH alone (p less than 0.01), and the reduction in the incidence of infection was evident even in patients showing severe granulocytopenia (p less than 0.01). Furthermore, the first fever after the onset of granulocytopenia in the OFLX regimen developed later than that in the control regimen (p less than 0.05). Clinically, the prophylactic efficacy was 92% for the OFLX regimen and 40% for the control regimen (p less than 0.01). These findings suggest that OFLX is a promising prophylactic agent following post-remission chemotherapy. Patient hemomyelogram findings similar to those of patients with other malignancies may imply that OFLX is widely effective in granulocytopenic patients taking aggressive chemotherapy.

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.

Survivin, a unique member of the inhibitor of the apoptosis protein (IAPs) family, is over-expressed in many cancers but not in normal differentiated adult tissues. Using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we investigated patterns of survivin gene expression in a group of 12 patients with chronic myeloid leukemia (CML) representing both chronic and blastic phases of the disease. All 6 patients in chronic phase CML were uniformly negative for the survivin transcript, in contrast to 4 Philadelphia chromosome-positive (Ph+) CML patients in blastic crisis, all of whom (100%) were positive for survivin with tangible levels of expression. However, survivin expression was markedly down-regulated in 2 atypical CML patients with Philadelphia chromosome-negative (Ph-) blastic crisis. Our data indicates that up-regulation of survivin expression may be involved in typical CML evolution from the chronic into the blastic phase of the disease.

Survivin is a member of the inhibitor of apoptosis protein (IAPs) family and considered to play a pivotal role in oncogenesis. We present the first report of survivin expression profile in myelodysplastic syndrome (MDS). Expression of survivin messenger RNA was evaluated by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with MDS and acute myeloid leukemia (AML). Eleven out of 12 patients with refractory anemia (RA) (91.6%), and all 3 patients with refractory anemia with excess blasts in transformation (RAEBt) (100%), were positive for survivin expression with the majority of cases showing abundant levels of the survivin transcript. On the other hand, expression of survivin was undetectable in the 4 patients with chronic myelomonocytic leukemia (CMMoL). The level and frequency of survivin expression in patients with refractory anemia were compared to those in patients with AML. Out of 12 patients with de novo AML, 5 patients (41.7%) showed detectable levels of survivin expression. Abundant survivin expression in RA was also confirmed by immunohistochemistry. In contrast, survivin was almost absent in two cases with aplastic anemia. We propose that high levels of survivin expression can serve as a reliable diagnostic marker of RA in MDS.

We describe a very rare case of a patient who presented with red cell aplasia that later developed into myeloproliferation with myelodysplasia and eventually leukemia. A 63-year-old man presented with anemia and reticulocytopenia in May 1997. A bone marrow examination revealed erythroid aplasia with normal production of myeloid cells and megakaryocytes with a normal karyotype. After the diagnosis of pure red cell aplasia was made, the patient was treated with prednisolone and then with cyclosporin A (CyA). Two weeks after the initiation of CyA treatment, the peripheral reticulocyte count began to increase with a regrowth of erythroid cells in the bone marrow. Meanwhile, the peripheral white blood cell and platelet counts also increased to more than 10,000/microL and 1,000,000/microL, respectively. Examination of a bone marrow aspirate in December 1997 revealed myelodysplastic changes with trisomy 8. Despite the discontinuation of CyA and the administration of 1-beta-D-arabinofuranosylcytosine stearyl monophosphate, leukemia developed in August 1998. In September 1998, the patient died of sepsis during a neutropenic period that followed remission-induction therapy. In the mechanism of pathogenesis, CyA may induce upon pure red cell aplasia a secondary myeloproliferative disorder with myelodysplasia and leukemia. An alternative possibility is that CyA reduces autoimmune-mediated suppression of the underlying stem cell disorder and that the result of this reduction is the manifestation of myeloproliferation and leukemia.

Aim: To assess clinical usefulness of an intermittent-flow blood cell separator in peripheral blood stem cell (PBSC) collection and transplantation. Results: the Haemonetics Multi Component System (Multi) was used to collect PBSC (52 aphereses in 17 patients). The mean processing blood volume and the mean PBSC yield were 7407 ml and 2.16 × 10 6 CD34+ cells/kg, respectively. When CD34+ cells exceeded 0.3% of the peripheral WBC, more than 2.0 × 10 6 CD34+ cells/kg could be collected by a single apheresis. Eight patients underwent PBSC transplantation after high-dose chemotherapy. Hematopoietic recovery was achieved in a median period of 10 days. Conclusions: (1) A single-arm, light-weight machine has sufficient capability to collect PBSC. (2) The percentage of CD34+ cells in the peripheral WBC is a good predictor of the CD34+ cell yield of the collection.

We examined the effect of PSC 833, a non-immunosuppressive cyclosporin analogue, on the cytotoxicity, accumulation and retention of idarubicin (IDA) and its 13-dihydro metabolite, idarubicinol (IDAol). P-glycoprotein (PGP)-overexpressing multidrug-resistant K562/D1-9 cells were used for these studies. PSC 833 had no effect on the cytotoxicity, intracellular accumulation, or retention of IDA and IDAol in the parent K562 cells. However, intracellular accumulation of IDA and IDAol in K562/D1-9 cells after a 60-min incubation was restored by 0.4 microM PSC 833 to 104% and 116%, respectively, of the level in parent K562 cells. The retention of IDA and IDAol in K562/D1-9 cells was also restored by 0.4 microM PSC 833. Consequently, 0.4 microM PSC 833 increased the sensitivity of K562/D1-9 cells to IDA and IDAol. The resistance index (RI) of IDA decreased from 20-fold to 4.0-fold, and the RI of IDAol decreased from 104-fold to 1.5-fold. These results suggest that the combination of IDA and PSC 833 may be effective in reversing PGP-mediated multidrug resistance in leukemia cells.

We investigated the cytotoxicity and cellular pharmacology of idarubicin (IDA), idarubicinol (IDAol) and daunorubicin (DNR) in K562/VP-H2 cells, which show topoisomerase II-related multidrug resistance but do not overexpress P-glycoprotein. K562/VP-H2 cells were less resistant to IDA and IDAol than to DNR. There was no significant difference in the accumulation of each drug between K562 and K562/VP-H2 cells. The cleavage of DNA induced by each drug was decreased in K562/VP-H2 cells, however, the decrease in cleavage in K562/VP-H2 cells was less with IDA and IDAol than with DNR. These results suggest that IDA and IDAol have more cytotoxic potency than DNR in topoisomerase II-related multidrug-resistant leukemia cells.

Inosine-5’-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) is the enzyme that catalyzes the formation of xanthosine-5’-monophosphate from inosine-5’-monophosphate (IMP). In the purine de novo synthetic pathway, IMPDH is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides. Alterations in the activity of IMPDH and the levels of guanine nucleotides have been implicated in the regulation of cell growth and differentiation[1]. The addition of IMPDH inhibitors, such as mycophenolic acid and tiazofurin, to cultures induces terminal differentiation in a variety of human leukemia cells, including K562 erythroid leukemia cells, and HL-60 myeloid leukemia cells as well as human breast cancer cells and melanoma cells[2–4]. To verify the role of this enzyme in controlling differentiation, we determined the ability of specific IMPDH antisense oligomers to induce maturation in the K562 and HL-60 human leukemia cell lines. From these experiments, we concluded that a specific reduction in IMPDH results in inhibition of cell replication and induction of terminal differentiation in the two human leukemia cell lines.