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Objective Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). Methods Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. Results Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. Conclusions These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study., Darinaparsin shows good tolerability and potential efficacy for relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is recommended for phase II study.

Objective A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Methods Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. Results Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43–7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. Conclusions This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients., This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Objective Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma. Methods In total, six patients (follicular lymphoma: n = 3, chronic lymphocytic leukemia: n = 3) were enrolled to receive idelalisib 150 mg twice daily. Results No dose-limiting toxicities were reported. The most common adverse events were diarrhea (n = 5), gastritis (n = 3), insomnia (n = 3) and pyrexia (n = 3). The most common ≥grade 3 adverse events were diarrhea (n = 2), increased transaminase levels (n = 2) and decreased appetite (n = 2). The maximum idelalisib plasma concentrations (Cmax) were achieved at 2.50 h (range: 1.50–4.00 h). The mean idelalisib plasma concentrations decreased over time but remained detectable in most patients at 12 h. All enrolled patients underwent efficacy evaluation by investigators, and five patients (follicular lymphoma: n = 2, chronic lymphocytic leukemia: n = 3) achieved partial response. The median duration of partial response was 14.5 months (range: 3.7–31.3 months). Conclusion Idelalisib 150 mg twice daily was considered tolerable in Japanese patients with follicular lymphoma or chronic lymphocytic leukemia. (Clinical trial registration: NCT02242045)

Objective HBI-8000 (tucidinostat) is a novel, oral histone deacetylase inhibitor that selectivity inhibits Class I (histone deacetylase 1, 2, 3) and Class II (histone deacetylase 10) with direct anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It has been approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma. Methods This multicenter, prospective phase I dose-escalation trial evaluating the safety of twice weekly HBI-8000 was conducted in Japan. Eligible patients had non-Hodgkin’s lymphoma and no available standard therapy. The primary endpoint was maximum tolerated dose; secondary endpoints included anti-tumor activity, safety and pharmacokinetics. Results Fourteen patients were enrolled in the study. Twelve patients were assessed for dose-limiting toxicity: six patients in the 30 mg BIW cohort had no dose-limiting toxicitys; two of six patients in the 40 mg BIW cohort had asymptomatic dose-limiting toxicitys. Treatment was well tolerated; adverse events were predominantly mild to moderate hematologic toxicities and were managed with dose modification and supportive care. Thirteen patients were included in the efficacy analysis. Objective response was seen in five of seven patients in the 40 mg BIW cohort; three partial responders had adult T-cell leukemia-lymphoma. In the 30 mg BIW cohort, three of six patients had stable disease after the first cycle. Conclusions Treatment with HBI-8000 30 and 40 mg BIW were well-tolerated and safe, with hematological toxicities as expected from other studies of histone deacetylase inhibitor. The maximum tolerated dose and recommended dosage for phase II studies of HBI-8000 is 40 mg BIW. Preliminary efficacy results are encouraging.

Background Many patients with classical Hodgkin lymphoma show increased programmed death-1 ligand expression in Reed–Sternberg cells. We report the final results of a phase II study of nivolumab, an anti-programmed death-1 monoclonal antibody, in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Methods Japanese patients with previously treated classical Hodgkin lymphoma (aged ≥ 20 years) were administered nivolumab (3 mg/kg on Day 1 of 14-day cycles) until progressive disease, an unacceptable adverse event, or another clinically relevant reason. Treatment could continue beyond progressive disease at the investigator’s discretion in selected patients. Results Seventeen patients (median age: 63.0 years) were enrolled. The median follow-up was 38.8 months. One patient with non-Hodgkin lymphoma was excluded from efficacy analyses. The centrally assessed overall response rate in 16 classical Hodgkin lymphoma patients was 87.5% (95% confidence interval = 61.7–98.4%) and the disease control rate was 93.8% (95% confidence interval = 69.8–99.8%). The median (95% confidence interval) duration of response and progression-free survival were 8.5 (2.4–12.6) and 11.7 (1.8–42.3) months, respectively. The 3-year overall survival rate was 80.4% (95% confidence interval = 50.6–93.2%). Nivolumab was continued beyond progressive disease in seven patients; six were alive at the data cut-off. Adverse drug reactions occurred in all 17 patients with grades 3–4 adverse drug reactions in eight patients and no grade 5 adverse drug reactions. Pulmonary toxicities occurred in five patients; four of these occurred ≥17 months after starting nivolumab. Conclusion Nivolumab is effective and tolerable in Japanese relapsed or refractory classical Hodgkin lymphoma patients. Continued monitoring may be necessary to detect late-onset pulmonary toxicities. Clinical trial registration JapicCTI-142755 (Japan Pharmaceutical Information Center)., We report the final results of a phase II study of nivolumab in Japanese patients with classical Hodgkin lymphoma. Nivolumab was effective with reductions in tumor size in responders and was tolerable.

Objective To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Methods Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics. Results The major treatment-emergent adverse events were anemia, neutropenia (6/6 patients each) and thrombocytopenia (5/6 patients) in hematologic adverse events, and nausea, vomiting, decreased appetite, cytomegalovirus test positive and pyrexia (4/6 patients) in non-hematologic adverse events. As serious adverse events, cytomegalovirus infection, pulmonary tuberculosis and diffuse large B-cell lymphoma were reported in 1/6 patient each. The overall response rate was 33% (95% confidence interval: 4-78) (1/6 patient each achieved complete response and partial response, respectively) and 3/6 patients had stable disease and 1/6 patient had progressive disease. The median time to response was 2.9 months. After last intravenous dosing (Week 12) of alemtuzumab 30 mg every other day three times a week, Cmax, tmax, AUC0-τ and t1/2 were higher and CL and Vss were lower than the values observed after the first dose. Conclusions The efficacy, safety and pharmacokinetics results observed with alemtuzumab in Japanese patients were generally similar to those reported in overseas clinical studies. Alemtuzumab at 30 mg by intravenous infusion every other day three times a week for 12 weeks should be safe and effective similarly in Japanese B-cell chronic lymphocytic leukemia patients. Clinical trial registration no NCT00923182.

Objective: Classical Hodgkin lymphoma shows a peak incidence at 15–35 years, and a second peak in elderly patients; however, pathological characteristics of elderly patients with classical Hodgkin lymphoma have not been analyzed enough. Methods: In a total of 154 patients with classical Hodgkin lymphoma, we analyzed the clinicopathological characteristics of classical Hodgkin lymphoma patients aged ≥40 years old, with special reference to the incidence, histopathology and outcome of patients with composite classical Hodgkin lymphoma. Results: Of 154 patients with classical Hodgkin lymphoma, 50 (32%) were ≥40 years old. The 5-year progression-free and overall survival rates were 59 and 86%, respectively. Thirty-eight patients (76%) had non-composite classical Hodgkin lymphoma, 10 patients (20%) had composite (6 simultaneous and 4 consecutive) classical Hodgkin lymphoma and B-cell non-Hodgkin lymphoma and 2 patients (4%) had methotrexate-associated classical Hodgkin lymphoma. Of 10 patients with composite classical Hodgkin lymphoma, composite lymphomas were detected throughout the staging procedure of the upper gastrointestinal tract or bone marrow in 4 patients. Fluorescence in situ hybridization revealed that the composite lymphomas of 4, 1 and 5 patients were related, unrelated and of unknown correlation status, respectively. The treatments after the diagnosis of a classical Hodgkin lymphoma component varied, and three patients died of lymphoma. Conclusions: We found that the incidence of composite classical Hodgkin lymphoma in patients ≥40 years old was 20%. Correct diagnosis and optimal treatment for patients with composite classical Hodgkin lymphoma and B-cell non-Hodgkin lymphoma is highly important in this patient population.

Objectives: Ofatumumab is a human IgG1k monoclonal antibody that targets a membraneproximal epitope encompassing the small and large loops of CD20. This Phase I study evalu-ated the safety, tolerability, efficacy and pharmacokinetics of ofatumumab monotherapy inJapanese patients with relapsed/refractory B-cell chronic lymphocytic leukemia and smalllymphocytic lymphoma.Methods: Ofatumumab was administered intravenously weekly for a total of eight doses(dose escalation: 500 and 1000 mg). Six patients (two chronic lymphocytic leukemia and foursmall lymphocytic lymphoma) were enrolled into two dose cohorts (500 mg, three patients;1000 mg, three patients). All six patients received 300 mg ofatumumab at the first infusionand either 500 or 1000 mg at seven subsequent weekly infusions.Results: No dose-limiting toxicities or serious adverse events were observed. Grade 3–4adverse events observed were grade 3 lymphocytopenia (n ¼ 1) and neutropenia (n ¼ 1).Grade 1–2 infusion-related adverse events leading to temporary interruption of ofatumumabinfusion were observed in all six patients on the first infusion day, and all patients completedthe planned eight infusions. The overall response rate was 50% (3/6).Conclusions: Ofatumumab was well tolerated at doses up to 1000 mg and showed prelimin-ary evidence of activity in relapsed or refractory chronic lymphocytic leukemia/smalllymphocytic lymphoma, warranting further investigations. This study was registered atClinicalTrials.gov (NCT00742144).Key words: ofatumumab – chronic lymphocytic leukemia – small lymphocytic lymphoma – CD20 –monoclonal antibody

Objective To evaluate the efficacy and safety of intensive post-remission chemotherapy for untreated patients aged 15-69 years with adult acute lymphoblastic leukemia and lymphoblastic lymphoma in a multicenter Phase II study. Methods The chemotherapy regimen consisted of induction, post-remission and maintenance for 2 years. The primary endpoint was 5-year progression-free survival, and secondary endpoints included complete remission rate, overall survival and adverse events. Among 115 patients enrolled, 108 eligible patients [median age, 33.5 years (range, 15-69)] including 96 acute lymphoblastic leukemia and 12 lymphoblastic lymphoma were assessed. Other major characteristics were male 50%, T-cell phenotype 21%, Philadelphia chromosome 22%, B-symptom+ 35% and performance status 2/3 22%. Results Eighty-seven patients achieved complete remission (81%; 95% confidence interval 72-88%), while five (5%) died during the chemotherapy protocol. The median overall survival and progression-free survival were 1.8 years (95% confidence interval, 1.5-2.6) and 1.2 years (95% confidence interval, 0.8-1.6), respectively. Their 5-year overall survival and progression-free survival were 29 and 28%, respectively. The 5-year overall survival of 31 patients who underwent allogeneic (n = 19) or autologous (n = 12) stem cell transplantation during first complete response was 51%. Major non-hematologic toxicities of Grade 3 or greater were infections (21%) and pulmonary complications (6%). When compared with the investigators' previous Phase II trials, JCOG9402 improved progression-free survival and overall survival when compared with JCOG8702; however, it did not show improvement when compared with JCOG9004. Conclusions Although the intensified induction and post-remission chemotherapy was feasible and 28% of the patients with adult acute lymphoblastic leukemia or lymphoblastic lymphoma achieved long-term progression-free survival, JCOG9402 did not show improvement.

The Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group (JCOG) was initiated in 1978 by five institutions and now has 47 members. JCOG-LSG has focused on combined modalities, dose intensification and the incorporation of new agents for major disease entities of lymphoid malignancies. More than 30 trials including 10 randomized trials have been conducted for aggressive non-Hodgkin's lymphoma (NHL), adult T-cell leukemia-lymphoma (ATL), lymphoblastic lymphoma/acute lymphoblastic leukemia, Hodgkin's lymphoma (HL), multiple myeloma, NK/T-NHL and indolent B-NHL, and correlative epidemiological and pathological studies have been performed on human T-lymphotropic virus type-I and T/B cell phenotypes. The first trials for aggressive NHL revealed significant differences in the prognosis of ATL, non-ATL T-NHLs and B-NHLs, establishing a subclassification of ATL, and leading to the establishment of standard therapies for ATL and localized nasal natural killer/T-NHL. Recently, for B-NHLs including diffuse large B-cell lymphoma, mantle cell lymphoma, and indolent B-NHLs, regimens incorporating rituximab have been evaluated. The JCOG-LSG trials for HL led to the approval of dacarbazine for the National Health Insurance in Japan. The multicenter trials by the JCOG-LSG combining new modalities such as molecular-targeting agents will contribute to further improvements in the treatment of lymphoid malignancies.

A multicenter phase III study for untreated multiple myeloma was conducted to investigate a switch-induction chemotherapy with melphalan-prednisolone and vincristine-doxorubicin-dexamethasone followed by randomization on maintenance therapy for patients achieving plateau. Between November 2002 and November 2005, 34 patients were registered. The study was closed early because of poor accrual. Thirty-three eligible patients, with a median age of 65 years (range: 47-77 years) were analyzed for the secondary purpose. For induction therapy, 16 patients were treated with vincristine-doxorubicin-dexamethasone and 17 with melphalan-prednisolone initially. In eight cases, induction therapy was switched because of a poor response. Both regimens were well tolerated, but neutropenia, anorexia, constipation and infection with neutropenia were more frequent for vincristine-doxorubicin-dexamethasone. Best response rates were 44% (95% confidence interval, 20-70) and 47% (95% confidence interval, 23-72), respectively, for vincristine-doxorubicin-dexamethasone and melphalan-prednisolone. Vincristine-doxorubicin-dexamethasone/melphalan-prednisolone switch-induction therapy might be feasible and effective for Japanese patients with multiple myeloma.

Objective: The efficacy and safety of weekly administration of epoetin beta (EPO) for chemotherapy-induced anemia (CIA) patients was evaluated. Methods: One hundred and twenty-two patients with lung cancer or malignant lymphoma undergoing chemotherapy were randomized to the EPO 36 000 IU group or the placebo group. Hematological response and red blood cell (RBC) transfusion requirement were assessed. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire. Results: Mean change in hemoglobin level with EPO increased significantly over placebo (1.4+1.9 g/dl versus 20.8+1.5 g/dl; P , 0.001). The proportion of patients with change in hemoglobin level 2.0 g/dl was higher for EPO than those for placebo (P , 0.001). After 4 weeks of administration, the proportion of RBC transfusion or hemoglobin level ,8.0 g/dl was significantly lower for EPO than those for placebo (P ¼ 0.046). The changes in the FACT-An total Fatigue Subscale Score (FSS) were less deteriorated with EPO than those with placebo. Progressive disease (PD) did not influence the change in hemoglobin level but there was less decrease in FSS in non-PD patients. No significant differences in adverse events were observed. Thrombovascular events and pure red cell aplasia related to EPO were not observed. Retrospective analysis of survival showing the hazard ratio of EPO to placebo was 0.94. Conclusion: Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period.

Objective: Follicular lymphomas (FLs) occur commonly in the lymph nodes, and duodenal FL (DFL) is reported to be rare. Methods: We analysed the clinical, morphological, immunohistochemical and genetic features of 26 cases of DFL. Primary DFLs and systemic FLs that involved the duodenum at any point during the clinical course were included in the analysis. Results: Typically, primary DFLs (14 cases) were found incidentally at routine medical check-ups, whereas involvement of the duodenum by systemic FLs (12 cases) was found through staging procedures. All cases involved the second portion of the duodenum. Helicobacter pylori infection was common (71%). In all cases, the histologic grade was low (either grade 1 or 2), and CD20, CD10 and Bcl-2 were positive by immunohistochemistry. Immunoglobulin heavy chain gene (IGH) and bcl-2 gene (BCL2) fusion was frequently shown by fluorescence in situ hybridization (FISH) analysis: nine of 12 cases (75%) of primary DFL and 10 of 12 cases (83%) of systemic DFL were positive. Treatment regimens employed were rituximab (R) plus chemotherapy (10), R (6), chemotherapy (3), irradiation (3) and the other three patients were subjected to observation. After a median follow-up duration of 40 months (ranging 11‐96 months), 17 patients were alive without disease, seven were alive with disease and one had died of lymphoma. Conclusions: Primary DFLs resemble systemic and nodal FLs, except that the former has high incidence of early stage and low-grade histology. The duodenum appears to be a frequently involved extranodal site of FL with IGH/BCL2.

Background: Although primary ocular adnexal MALT (mucosa-associated lymphoid tissue ) lymphoma (POAML) is a recently recognized unique entity, its natural history, prognostic factors, behavior of progression and death, and standard initial management have not been fully elucidated. Methods: The data of 114 patients with histologically verified POAML who were treated at our institution between 1970 and 2003 were retrospectively analyzed. Results: With a median follow-up duration of 5.7 years (0.6‐34.0), estimated overall survival (OS) rate and progression-free survival (PFS) rate at 10 years was 89% and 57%, respectively. Thirteen (11%) patients died, but only three (3%) of them due to progressive lymphoma. Thirty-one (27%) patients progressed: eight who progressed at contra lateral sites were limited to those who had initially involved in the orbit (P ¼ 0.036) and their OS and PFS were significantly longer (P ¼ 0.035 and 0.039, respectively). Patients who initially received radiation-containing therapy were superior in PFS but not in OS to those initially treated with other modalities (P ¼ 0.016 and 0.091, respectively). When we compared the outcomes of the observation cohort and the immediate therapy cohort, there were no significant differences in OS and PFS (P ¼ 0.499 and 0.073, respectively). Conclusions: The majority of patients with POAML showed the behaviors of localized and indolent diseases. Our preliminary observation that no initial therapy is an acceptable approach for selected patients was confirmed. Considering the possible heterogeneity of POAML among initial sites, further investigations are warranted.

Monoclonal gammopathy of undetermined significance does not overexpress cluster of differentiation (CD) 56, but plasma cell myeloma frequently overexpressed it. However, plasma cell leukemia and extramedullary plasmacytoma usually down-regulate CD56 expression. Plasmacytoma, especially 'solitary plasmacytoma of bone', is difficult to diagnose as plasma cell neoplasm, because it occasionally appears similar to other bone tumors, both clinically and pathologically, and is rarely accompanied by monoclonal protein in the serum or urine. The present case was a patient with an osteolytic 'small round cell tumor' of the iliac bone, which also invaded the femora. An immunohistopathological finding of CD56 expression played a key role in making a diagnosis. The definitive diagnosis of plasmacytoma was made based on the electron microscopic findings. The plasma cells which infiltrated her sternum showed the same restriction to kappa light chain expression in their cytoplasms as that of the iliac bone tumor cells, but did not express CD56. Locally infiltrating osteolytic bone tumors should be examined for surface immunoglobulin light chains as well as CD56 expression when plasmacytoma is suspected.

The results of the clinical trials by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG) and those of the industry-supported trials mainly conducted by the members of JCOG-LSG are summarized. In the treatment of advanced aggressive non-Hodgkin's lymphoma (NHL), we investigated the efficacy of granulocyte colony-stimulating factor (G-CSF)-supported, dose-intensified strategies. Based on the results of a randomized phase II study (JCOG9505), we conducted a phase III study, JCOG9809, comparing CHOP and biweekly CHOP. However, JCOG9809 was terminated early based on the results of a planned interim analysis, because it was deemed highly unlikely that biweekly CHOP would be superior to standard CHOP. For aggressive ATL, a G-CSF-supported, dose-intensified, multi-agent regimen (JCOG9303; LSG15) showed superior efficacy to our historical controls. To establish a new standard for ATL, we conducted a phase III study, JCOG9801, comparing LSG15 and biweekly CHOP. To develop new agents for lymphoid malignancies, we focused on irinotecan hydrochloride, interferon-alpha, cladribine and oral fludarabine. Among them, cladribine and oral fludarabine are promising for indolent B-cell malignancies. The Japanese phase I and II studies of rituximab, a chimeric anti-CD20 monoclonal antibody, in relapsed indolent and aggressive B-NHL showed high efficacy with minimal toxicities, which led us to conduct combination studies with chemotherapy for B-NHL. In addition, a phase I study of a radiolabeled anti-CD20 antibody (ibritumomab tiuxetan) was completed in 2003, and a phase II study for indolent B-NHL will be initiated. The multicenter trials by the JCOG-LSG and industry-supported new agent studies will contribute to further improvement in the treatment of malignant lymphoma.

The Fifteenth International Symposium of the Foundation for Promotion of Cancer Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15-17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from Japan, presented the updated results of their research. After an overview of the classification of hematological malignancies, new findings on some disease entities based on novel immunophenotypic and molecular genetic features were presented. The results of gene expression profiling and BCL6 and C-MYC gene rearrangement in diffuse large B-cell lymphoma were presented and oncogenic mechanism of acute myeloid leukemia was discussed. In the treatment of non-Hodgkin's lymphoma and acute leukemia, the present consensus and future directions were discussed based on the results of multicenter trials in the USA and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and gastrointestinal stromal tumor was presented. Thereafter, promising results of active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20 radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were presented. Finally, recent advances in allogeneic hematopoietic stem cell transplantation were discussed, focusing on reduced-intensity preparative regimens. The recent advances in basic and clinical research on hematological malignancies would lead to further improvement in the prognosis and quality of life of patients suffering from leukemia or lymphoma.

Background Patients with acute lymphocytic leukemia (ALL) and those with lymphoblastic lymphoma (LBL) have overlapping clinical and immunophenotypic features and they have been treated with the same or very similar chemotherapy regimens. The goal of this multi-institutional phase II trial was to evaluate the therapeutic efficacy of a short-term, six-drug chemotherapy regimen for adult patients with untreated ALL or LBL. Methods Forty-six eligible patients, 41 with ALL and five with LBL, were treated with a short-term (planned total therapy duration; 36-38 weeks), simplified chemotherapy program; two courses of VEPA-L (vincristine, cyclophosphamide, prednisolone, doxorubicin, I-asparaginase plus intrathecal methotrexate and prednisolone) followed by four courses of M-VEPA (methotrexate plus VEPA), without the traditional maintenance therapy using daily 6-mercaptopurine and weekly methotrexate. Results Thirty-six (78%; 95% confidence interval 64-89%) of the 46 eligible patients achieved complete remission (CR). Among the 36 patients who achieved CR, four (11%) died of treatment complications, 26 (72%) relapsed and six (17%) remain alive in continuous CR. The median survival for all 46 eligible patients is 14 months and the median disease-free survival (DFS) for the 36 patients who achieved CR is 11 months. The estimate of the proportion of survival at 7 years of all 46 eligible patients is 15% at a median follow-up time of 96 months and that of DFS of the 36 patients achieving CR is 17% at a median follow-up time of 93 months. Subgroup analysis showed that an elevated serum C-reactive protein (CRP) level, age of 30 years or older, the presence of B-symptom and T-cell phenotype were likely to be associated with shortened survival. Although the observed CR rate (78%) is within the range of satisfaction, the long-term survival rate (15%) is inferior to those of published programs incorporating maintenance therapy. Conclusions A fraction of adult patients with ALL or LBL are curable with a short-term, six-drug chemotherapy regimen. However, this simplified therapy of shorter duration cannot be recommended.

Background The optimum dose of granulocyte colony-stimulating factor (G-CSF) for peripheral blood stem cell (PBSC) mobilization after disease-oriented, conventional-dose chemotherapy remains unknown. Methods A multicenter dose-finding study of glycosylated G-CSF (lenograstim) for the mobilization of PBSCs following adjuvant CAF chemotherapy (cyclophosphamide, doxorubicin and 5-fluorouracil) was performed in 38 patients with postoperative breast cancer. Each 10, ten and eight patients were sequentially allocated to one of the three dose groups (2, 5 and 10 micrograms/kg, respectively) of lenograstim. Lenograstim was administered subcutaneously (s.c.) daily from day 8 to the day of the last apheresis and CD34+ cells and colony-forming units-granulocyte macrophage (CFU-GMs) in peripheral blood were measured serially. Additionally, 10 patients who received adjuvant CAF chemotherapy alone also participated in the study, as a control. Results Lenograstim was well tolerated up to 10 micrograms/kg, except for one patient given 10 micrograms/kg who developed transient grade 3 hepatic enzyme elevation. The peak levels of CD34+ cells and CFU-GMs in peripheral blood showed dose-response relationships. The median peak CD34+ cells for the 0, 2, 5 and 10 micrograms/kg dose groups were 5.4, 34.3, 55.0 and 127.6 cells/microliter, respectively, and those of CFU-GMs for the 0, 2, 5 and 10 micrograms/kg dose groups were 0.01, 0.33, 1.32 and 3.30 CFU-GMs/microliter, respectively. Conclusions Considering the previous reports suggesting that a pre-apheresis number of 40-50 CD34+ cells/microliter in peripheral blood is highly predictive for achievement of more than 2.5 x 10(6) CD34+ cells/kg in a standard apheresis procedure of 10 litres, the optimum dose of lenograstim for PBSC mobilization following CAF chemotherapy in patients with postoperative breast cancer is 5 micrograms/kg/day s.c.

We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer.

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.

Eleven patients with hairy cell leukemia (HCL) were treated with YK-176 (2'-deoxycoformycin) at a dose of 5 mg/m2 by intravenous injection every week or every other week. Patients received a median of eight (range 4-19) injections of YK-176. Five patients had previously been untreated, four of whom had massive splenomegaly. Six patients had previously been treated, four with interferon-alpha (IFN-alpha) or IFN-alpha and chemotherapy and two with prednisolone. Two patients had had splenectomies. Five patients achieved complete remission (CR) and six, partial remission (PR) according to WHO criteria (remission rate 100%, 95% confidence interval (CI) 74-100%). All six neutropenic patients recovered > 1,500/microliters neutrophils, six of seven anemic patients recovered > 12.0 g/dl hemoglobin and five of nine thrombocytopenic patients recovered > 100,000/microliters platelets following the treatment. According to the response criteria for HLC, five patients achieved CR, two PR and four minor response. The overall remission (CR + PR) rate was 64% (95% CI 35-85%). The CR and PR have lasted from > 30 to > 718 days (median, > 281 days) so far with no relapses. Of four patients previously treated with IFN-alpha, two achieved CR and one, PR. All patients were alive with a median survival time of > 290 days from treatment (range > 50- > 763 days). The treatment was generally well tolerated. Mild to moderate nausea, vomiting, appetite loss and general fatigue were experienced in two patients, skin rash in one and a transient fever in three. YK-176 was a highly active agent in the treatment of HCL.

Background: The incidence of primary bone lymphoma (PBL) is so rare that many of its aspects remain unknown. A number of studies have been reported from Western countries, but only a few reports are available from Asia. Methods: We retrospectively analyzed 28 consecutive patients diagnosed with PBL initially treated at our hospital between 1995 and 2004. All patients underwent chemotherapy with half receiving radiotherapy as their initial treatment. A log-rank test was used in a univariate analysis to identify factors affecting overall survival. Results: Fifteen (54%) patients were male and 13 (46%) female with a median age of 47 (range: 5–81). Although 19 (68%) patients had diffuse large B-cell lymphoma (DLBCL), other histopathological subtypes (three B-lymphoblastic lymphoma, two anaplastic large cell lymphoma, two indolent B-cell lymphoma, one NK/T-cell lymphoma (NTCL) and one Hodgkin lymphoma) were also included. The pelvis was the most frequently involved site (54%). While 68% of patients had stage IV disease, none of them showed bone marrow involvement at their initial diagnosis. Despite 61% high intermediate-risk and high-risk patients based on the International Prognostic Index, the estimated 3-year overall and progression-free survival rates were 84% and 77%, respectively. Only ‘histopathological subtype (immunoblastic variant of DLBCL or NTCL versus others)’ and ‘response to initial treatment (progression versus remission)’ were factors significantly affecting overall survival. Conclusions: Although the total number of patients was relatively small, the detailed clinical data analyses presented here revealed several new characteristics of PBL and some aspects that may be unique to Japanese patients.

OBJECTIVE To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial. METHODS A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18,000 or 36,000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements. RESULTS Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36,000 IU group was significantly greater than that in the 9000 IU group (1.75 +/- 2.15 versus 0.04 +/- 1.98 g/dl; P = 0.009), and a significant dose-response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups. CONCLUSIONS Once-weekly epoetin-beta 36,000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.

Background Peripheral blood stem cell (PBSC) reinfusion has been widely used for hematopoietic reconstitution after high-dose chemotherapy. However, the optimal dose of granulocyte colony-stimulating factor (G-CSF) for PBSC mobilization in combination with chemotherapy for autograft remains unknown. Methods To find the optimal dose of glycosylated G-CSF (lenograstim) for PBSC mobilization in combination with chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), we conducted a dose-finding study on 43 newly diagnosed patients who had unfavorable prognostic factors. They received four to six courses of cyclophosphamide, doxorubicin, vincristine and prednisolone combined with lenograstim every 2 weeks (biweekly CHOP therapy). PBSC apheresis was started after the third course of biweekly CHOP therapy. Lenograstim was given daily from day 3 until the day of the last apheresis. The optimum dose of lenograstim was assessed based on mobilization efficacy and safety profiles at a daily single dose of 2, 5 and 10 microg/kg for eight patients in each level. Results The collected number of CD34+ cells in the first apheresis products was higher in the 5 microg/kg group than in the 2 microg/kg group (median, 4.22 x 10(6) vs 2.49 x 10(6) CD34+ cells/kg, P = 0.051). The highest dose of 10 microg/kg (median, 2.99 x 10(6) CD34+ cells/kg) failed to show a dose dependence in PBSC mobilization. The efficacy and safety of the 5 microg/kg dose were further confirmed in an additional 19 patients. Conclusions The present study suggests that the recommended dose of lenograstim for PBSC mobilization with CHOP therapy in untreated NHL is 5 microg/kg.

The majority of gastrointestinal lymphomas arise in the stomach, whereas lymphomas occurring in the intestine are relatively rare and a limited fraction of them show the T-cell phenotype with clinical manifestations similar to de novo celiac disease. Enteropathy-type T-cell lymphoma is extremely rare in Japan, presumably owing to the very low incidence of celiac disease among the Japanese population. Here, we report a 66-year-old Japanese male who was diagnosed as having enteropathy-type T-cell lymphoma preceded by diarrhea and intermittent bloody stool for over 1 year. He was admitted to our hospital as an emergency case because of panperitonitis due to intestinal perforation. After immediate partial small-bowel resection, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy was started. However, the disease was highly refractory and was exacerbated with leukemic transformation. Subsequent salvage chemotherapy could not be completed because of the formation of spontaneous jejuno-abdominal fistula, followed by fatal septic shock. Particular attention should be paid to the peculiar clinical manifestations of enteropathy-type T-cell lymphoma such as malnutrition, frequent intestinal perforation and refractoriness to chemotherapy.

G-CSF administration may not affect the rate of engraftment unless sufficient numbers of stem cells are transplanted. However, there might be some cases in which neutrophil recovery is delayed after stem cell transplantation despite a relatively fast recovery of platelet counts and total white blood cell counts. This delayed engraftment might be observed in either autologous or allogeneic stem cell transplantation. Here we report four cases with delayed neutrophil engraftment which subsequently improved with administration of a minimal dose of G-CSF. As the response occurred on the day following G-CSF administration, a mobilization defect is suspected to be the mechanism of this delayed engraftment.

Background Accumulation of data regarding therapy-related leukemia (TRL) or myelodysplastic syndrome (t-MDS) is critical for assessing the risk of developing such diseases and for subsequent decision-making processes for better treatment. Methods We evaluated the clinical characteristics of patients with TRL/t-MDS diagnosed at the National Cancer Center Hospital between January 1989 and September 1997. This report is concerned with those patients who initially had been treated with chemotherapeutic agents for breast cancer. Results Thirteen patients (median age, 55 years) developed TRL (n = 4) or t-MDS (n = 9). The median interval between the development of TRL/t-MDS and initial treatment was 94 months (range 23-190 months). For the primary therapy, all patients had received intense and prolonged treatment with cyclophosphamide (CPA) and/or anthracyclines including doxorubicin (DOX), with a median cumulative dose of 55 g/body (range 16.4-288.5 g) for CPA and 480 mg/m2 (range 395-625.5 mg/m2) for DOX. Seven patients were subsequently treated by chemotherapy and one received an allogeneic bone marrow transplantation. Conclusions Clinicians must remain alert to the risks associated with unproven medical practices which include long-term administration of alkylating agents. Selected patients with TRL/t-MDS may respond to intense salvage combination chemotherapy.

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +/- 300.4 nM x h at Level 1 (n = 3) to 3411.3 +/- 341.0 nM x h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.

The incidence of follicular lymphoma in Japan is far lower than that in western countries, and no large-scale clinicopathologic studies on this neoplasm have been conducted in Japan. We reviewed histopathological specimens from 118 of 135 patients who had been diagnosed as having follicular lymphoma between 1968 and 1993. Prognostic factors influencing survival were analyzed using univariate and multivariate analyses. Factors that were independently significant upon multivariate analysis were incorporated into a predictive model. Ninety-three patients (78.8%) had a confirmed diagnosis of follicular lymphoma. Twenty-one of the remaining 25 patients were categorized as having other lymphoma subtypes, and four patients showed indefinite findings or those suggesting diseases other than lymphoma. Major characteristics of the 93 patients with follicular lymphoma were a median age of 53 years (20-85); 59 males (63%) and 34 females (37%); small cleaved cell type in 33 (35%), mixed cell type in 41 (44%) and large cell type in 19 (20%); stage I/II in 41 (44%) and stage III/IV in 50 (54%). Overall survival was 71% at 5 years, 58% at 10 years, and 43% at 15 years with a median survival of 13.3 years. Multivariate analysis revealed that two variables, age (>60) (P=0.001) and the serum LDH level (>1 x normal value) (P=0.026), were unfavorably significant prognostic factors influencing survival. The predictive model using these two variables identified three risk groups with estimated five-year survival rates of 88.5%, 56.8%, and 31.5%. Age and serum LDH were significant predictors of survival in Japanese patients with follicular lymphoma. Our predictive model may provide a basis for future therapeutic trials against follicular lymphoma in Japan.

We investigated the occurrence of hemorrhagic cystitis in 30 consecutive adult patients undergoing bone marrow transplantation (BMT) for hematological and non-hematological malignancies. Ten patients with hematological malignancies received allogeneic BMT, and twenty patients, seven with hematological and 13 with non-hematological malignancies, received autologous BMT. All 30 patients received high-dose cyclophosphamide-containing regimens (120 mg/kg in 16, 200 mg/kg in one, 6000 mg/m2 in 13) as preparative therapies. They all received 2-mercaptoethane sulphonate sodium (mesna) combined with hyperhydration 3 liter/day as prophylaxis for hemorrhagic cystitis. Bladder irrigation was not performed. Overall, five patients (16.7%) developed hemorrhagic cystitis; early-onset (within 48 hours of the end of the high dose chemoradiotherapy) hemorrhagic cystitis occurred in one (3.3%; 95% confidence interval, 0.6-16.7%) and late-onset occurred in four (13.3%; 95% confidence interval, 5.3-29.7%). In three of the four late-onset cases, adenovirus was isolated from the urine specimens at the onset of the hemorrhagic cystitis. Among the 13 patients with non-hematological malignancies receiving autologous BMT, one with recurrent breast cancer developed late-onset hemorrhagic cystitis associated with adenovirus type 11. We conclude the prophylactic measure with mesna and hyperhydration to be effective enough to prevent cyclophosphamide-induced hemorrhagic cystitis of early onset. Some BMT recipients, however, even those with non-hematological malignancies undergoing autologous BMT, develop late-onset hemorrhagic cystitis in which adenovirus is considered a principal causative agent.

YK-176 is a newly isolated 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, produced by Aspergillus nidulans. In a cooperative phase I study, YK-176 was administered to 22 patients, comprising 18 with adult T-cell leukemia-lymphoma (ATL), two with cutaneous T-cell lymphoma (CTCL), one with lymphoblastic lymphoma of T-cell type and one with carcinoma of the uterine cervix. Doses of YK-176 ranged from 3.0 to 9.0 mg/m2 and were given intravenously for three consecutive days. General malaise, anorexia, nausea, vomiting and low grade fever were frequently encountered, but were transient and not dose-related. At all dose levels hematological toxicities were mild. Two of seven patients receiving 7.0 mg/m2 for three consecutive days developed hepatocellular enzyme elevations (grade 2) and one patient, proteinuria (grade 2). One of two patients given 9.0 mg/m2 for three consecutive days manifested a life-threatening (grade 4) disturbance of consciousness and dyspnea, presumably ascribable to the drug-related toxicity of YK-176. The results suggest that 7.0 mg/m2 i.v. for three consecutive days is the maximum acceptable dose of YK-176. Central nervous system, pulmonary and possibly renal toxicities appeared to be dose-limiting. Out of the 20 patients evaluable for therapeutic response, partial remissions were observed in four, three with ATL and one with CTCL, who received less than 7.0 mg/m2 for three consecutive days. We conclude that YK-176 is an active agent against ATL at doses that may not be associated with prohibitive toxicity. A starting dose of 5.0 mg/m2 for three consecutive days is recommended for further phase II studies on ATL.

Among 262 inpatients with hematologic diseases who were referred for chemotherapy or immunosuppressive therapy between January, 1985, and December, 1989, nine (3.4%) patients, including two with Hodgkin's disease (HD), three with acute myeloblastic leukemia, one with chronic myelogenous leukemia, two with multiple myeloma and one with aplastic anemia, were found to be hepatitis B virus (HBV) carriers before their chemotherapy began. All six HBV carriers who received chemotherapy containing glucocorticoid showed mild-to-moderate elevations in serum transaminase levels after the chemotherapy. Five showed a rise in titer of the hepatitis B surface antigen, HBsAg. In contrast, three HBV carriers not receiving glucocorticoid showed no change in serum transaminase after chemotherapy. One HBV carrier with HD suffered from severe icteric hepatitis after the withdrawal of multiagent chemotherapy containing glucocorticoid. The HBV-DNA polymerase rose markedly and was accompanied by a marked rise in titer of HBsAg. The results warn us to keep in mind the possibility of glucocorticoid inducing an activation of HBV infection, which may result in severe hepatitis in some HBV carriers. Although further investigation is required, it is recommended that HBsAg-positive patients with hematologic malignancies should, if possible, be treated without glucocorticoid.

A 17-year-old male patient with T-cell type lymphoblastic lymphoma in complete remission underwent high dose chemotherapy (busulfan 16 mg/kg and cyclophosphamide 120 mg/kg) followed by autologous bone marrow transplantation (ABMT). The patient had been taking oral acyclovir (200 mg x 5) daily from seven days prior to the ABMT (day -7). On day +24, he complained of epigastralgia and general malaise, and the next day his GOT and GPT rose to 570 U/l and 397 U/l, respectively. Although he had no mucocutaneous lesions, hepatitis caused by a herpes virus was suspected, and high dose intravenous acyclovir (10 mg/kg x 3/day) was immediately started. His GOT, GPT and total bilirubin reached peaks of 2,870 U/l on day +26, 1,830 U/l on day +27 and 10.3 mg/dl on day +39, respectively, and rapidly improved thereafter. Serological analyses on IgG antibody titers to herpes simplex virus type 1 using an enzyme-linked immunosorbent assay revealed specific increases (454-fold before transplantation to 3,830-fold on day +46). Antiviral antibody titers to cytomegalovirus, varicella-zoster virus and Epstein-Barr virus showed no significant changes. The serologic markers of hepatitis B virus, hepatitis A virus and hepatitis C virus were all negative. The results indicate the patient's severe icteric hepatitis to have been caused by a reactivation of herpes simplex virus type 1 due to immunosuppression after high dose chemotherapy with ABMT. It is suggested that prompt commencement of high dose intravenous acyclovir is required to treat severe herpes simplex virus hepatitis affecting immunocompromised patients.

A 49-year-old man developed adult T-cell leukemia (ATL) and acute myeloblastic leukemia (AML) at the same time. Using Southern blotting analysis, the leukemic cells of the ATL were found to contain the human T-cell leukemia virus type I (HTLV-I) proviral genome, whereas those of the AML did not, indicating the HTLV-I not to be associated with the AML oncogenesis. At the initial presentation, the serum anti-HTLV-I antibody was judged on screening by a routine particle-agglutination (PA) test and an indirect immunofluorescence assay (IF) to be negative. By Western blotting analysis, however, the serum was proved to be positive for anti-HTLV-I antibody. These results indicate that a routine PA-test and an IF may show false negative reactions on very rare occasions of low antibody titer. This is the first report of a coincidence of ATL with another type of leukemia.

Tumor cells suspensions prepared from 129 B- or non-T cell malignancies were investigated with a panel of 10 monoclonal antibodies and conventional surface marker techniques. Surface immunoglobulin (sIg) and B1 antigen proved to be the most useful markers for B-cell lineage. Six major subtypes of acute lymphoblastic leukemia (ALL) of non-T cell nature are now recognized by these immunological techniques, including null-ALL, Ia-ALL, lymphoid stem cell ALL, pre-pre-B ALL, pre-B ALL and B-ALL. In cases of chronic leukemias and lymphomas of non-T cell nature, 80% of the tumor was defined by sIg and 88% by B1 antigen as definitely of B-cell lineage. The clonal character was also defined in 68% of the tumor on the basis of the detection of predominant single light chain in sIg. Ia-like antigen was detected in almost all cases (96%). Leukemic cells from all cases of chronic lymphocytic leukemia (CLL), chronic lymphosarcoma cell leukemia (CLsCL) and hairy cell leukemia (HCL) reacted with OKIa1 and anti-B1, and leukemic cells from most of them with anti-pan T monoclonal antibody (10.2). In more than half of CLL and CLsCL, leukemic cells were reactive with J5, OKM1, 9.6 and OKT8, but not with OKT3, OKT4 and OKT6. HCL cells had almost the same reactivity with these monoclonal antibodies as CLL and CLsCL cells except that J5 remained unreactive. These results indicated that Japanese CLL, CLsCL and HCL were different from Western ones at least with respect to surface marker characteristics. In cases of lymphomas, heavy chains of sIg were expressed in polyclonal fashion, especially in follicular lymphoma and diffuse lymphomas of medium sized cell type and large cell type, indicating that lymphomas of these types may originate from follicular center cells of the heavy chain switching stage. Anti-T monoclonals were also reactive with lymphoma cells. In about half of follicular lymphomas and diffuse lymphomas of the medium sized cell type, lymphoma cells reacted with 10.2, and less frequently with 9.6, OKT4 and OKT3. On the other hand, only in one or two cases of diffuse lymphoma of the large cell type and of immunoblastic sarcoma (IBS), did tumor cells react with 10.2 and 9.6, but this was exceptional. In more than 25% of IBS, tumor cells also reacted with OKT8, but not with OKT4 and OKT3. These results indicated that anti-T monoclonals are no longer specific for T-cell lineage.(ABSTRACT TRUNCATED AT 400 WORDS)

We report an asynchronous bilateral malignant lymphoma of the breast, in a 56-year-old woman, presenting unusual clinical signs and histological features. The patient, who had a family history of breast cancer, had undergone a standard right radical mastectomy four years previously for a non-epithelial malignant tumor. At that time, the tumor was thought to be a stromal sarcoma, because some of the neoplastic cells were elongated or vacuolated. The patient recently became aware of a rapidly growing tumor of the left nipple without erosion or pain. This tumor underwent biopsy, and the histological examination showed a non-Hodgkin's lymphoma of diffuse mixed type. Staging procedures demonstrated no sign of generalized disease. Following a modified left radical mastectomy for optimal local control and accurate staging, adjuvant chemotherapy consisting of vincristine, cyclophosphamide, prednisolone and doxorubicin was initiated. Immunohistochemical staining for PAN-B and leucocyte common antigen revealed both tumors to be malignant lymphomas of B-cell type, and the first lymphoma of the right breast was thought to be showing 'signet ring' cell change. Since the two tumors were morphologically quite different from each other, it was suggested that they were asynchronous bilateral primary malignant lymphomas; however, the possibility remains that the recent left breast tumor is a recurrence of the malignant lymphoma of the right breast. The patient is currently disease-free, 10 months after surgery.

Whether Castleman's disease is primarily hyperplastic or neoplastic in nature is a matter of controversy; however, the classical localized form has been thought clinically benign in itself, because it can be cured by local therapy. Recently, a multicentric form of the disease has been reported and has received attention because of its aggressive clinical course and high incidence of developing malignant lymphoma. Here, we describe a case of multicentric Castleman's disease which occurred in a 24-year-old Japanese man. To ascertain whether a monoclonal population was present or not, we performed a molecular genetic analysis of the genes encoding the T-cell receptor and the immunoglobulin, as well as a conventional immunohistochemical analysis. Using these sensitive methods, no monoclonal population could be found. The findings suggest that our case represents a reactive rather than a neoplastic disorder.