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Soluble Fas (sFas) in the serum is believed to be able to inhibit apoptosis of lymphocytes. It has been reported that the serum sFas level is increased in various diseases, including malignant lymphoma and systemic lupus erythematosus. We studied the association between sFas and the prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL). Compared with normal controls, the serum sFas level was increased significantly in patients with aggressive NHL and adult T cell leukemia/lymphoma. Among patients with aggressive NHL, the complete remission rate was significantly decreased in the subgroup having high serum sFas levels. Both the overall survival rate and the disease-free survival (DFS) rate were significantly lower for this subgroup than for patients with low serum sFas levels. The 5-year survival rates estimated by the Kaplan-Meier method for patients with high and low serum sFas levels were 27.6% and 68.3%, respectively (P = 0.0001). The 5-year DFS rates estimated for patients with high and low serum sFas levels were 44.7% and 71.9%, respectively (log-rank test: P = 0.0023, and generalized Wilcoxon test: P = 0.0014). Among patients with a low and low-intermediate risk group according to the International Prognostic Index (IPI), the 5-year survival rates for low and high serum sFas subgroups were 72.8% and 42.0%, respectively, showing a significant difference (Wilcoxon test: P = 0.0163, log-rank test: P = 0.0115). Among patients with a high-intermediate and high risk group, the 5-year survival rates for low and high serum sFas subgroups were 51.6% and 17.4%, respectively, again showing a significant difference (Wilcoxon test: P = 0.0001, log-rank test: P = 0.0002). Multivariate analysis of a series of prognostic factors, including the five used to calculate the IPI, showed that the serum sFas level was an independent prognostic factor for the overall survival. Based on these results, a serum sFas level of 10 ng/ml or more can be considered to indicate a poor prognosis in patients with advanced NHL, and this finding may be useful for developing strategies for further treatment.

Twenty cases of interstitial pneumonia secondary to treatment with granulocyte colony-stimulating factor (G-CSF) were reviewed. Their interstitial pneumonia had the following features: (a) it occurred predominantly in patients aged 60 years or older; (b) it was prevalent among patients with haematological malignancies, particularly non-Hodgkin's lymphoma; (c) in all patients G-CSF was given after anti-cancer agents with potential to affect the lungs; (d) at the onset, many patients had symptoms such as dyspnoea and fever; and (e) the leucocyte (neutrophil) count as well as lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels were usually higher than normal at the onset. These findings indicate that, when G-CSF is used in combination with pneumotoxic anti-cancer agents, respiratory function should be monitored before and during treatment. If the leucocyte (or neutrophil) count and/or LDH and CRP increase suddenly in association with dyspnoea and fever during administration of G-CSF, interstitial pneumonia should be suspected. Accordingly, a chest radiograph and pulmonary functional tests should be performed promptly. If a diagnosis of interstitial pneumonia is made, steroid pulse therapy should be commenced immediately. Images Figure 1

THP-COPBLM including pirarubicin (THP) , which is thought to be less toxic than doxorubicin, was used to treat non- Hodgkin’s lymphoma (NHL) and the remission rate and adverse effects were studied in 26 patients older than 70 years. Complete remission (CR) was achieved in 19 patients (73.1%) and partial remission in three (11.5%). Classified by stages, CR was achieved in seven out of nine stage II patients and 12 out of 17 stage III, IV patients. The 2-year survival rate was 60.3%. Grade 3 or higher adverse effects included leukopenia in eight patients (30.8%), anemia in three (11.5%), thrombocytopenia in two (7.7%) and nausea/vomiting in 1 (3.8%). The THP-COPBLM regimen appears useful for the treatment of NHL in elderly patients. The regimen was seldom associated with gastrointestinal symptoms and cardiotoxicity. Despite the administration of granulocyte colony-stimulating factor (G-CSF), however, the white blood cell count decreased in many patients, suggesting the necessity for further study of this regimen to modify the dose of THP.

Primary vaginal non-Hodgkin's lymphomas (NHL) are rare, and are clinically difficult to differentiate from inflammatory diseases or vaginal cancer. Here, we present such a case in a 74-year-old woman complaining of fever and difficulty with urination. Pelvic examination revealed a tumor involving most of the vaginal wall, and pelvic MRI demonstrated vaginal wall thickening. A biopsy of this lesion confirmed NHL (diffuse large B-cell lymphoma), and the patient was admitted. Abdominal CT and MRI detected a vaginal tumor, and Ga scintigraphy confirmed accumulation in the pelvis, but no abnormalities were seen in other areas. Therefore, the patient was diagnosed as having NHL at clinical stage IB with low-intermediate risk (international prognosis index) (LDH 1,309 IU/L). The patient underwent three courses of CHOP therapy followed by radiotherapy, and complete remission was achieved. Primary vaginal NHL often affects women younger than 50 years of age, and abnormal hemorrhage is the initial symptom in many cases. There have been a number of reports of long-term survival following appropriate early chemotherapy and radiation therapy, suggesting that early diagnosis and treatment based on vaginal biopsy findings greatly influence the prognosis.

Soluble interleukin-2 receptor (sIL-2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non-Hodgkin's lymphoma (NHL). The present study demonstrated that the sIL-2R level was high in the following groups of patients with aggressive NHL; those agedor = 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL-2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low-intermediate (L-I) risk groups with an sIL-2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL-2R level could be particularly useful for identifying patients with a poor prognosis among the L and L-I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL-2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL-2R level is a significant independent prognostic factor in patients with aggressive NHL.

Most chromosomal abnormalities associated with breakage at 11q23 in acute leukaemia involve the MLL gene, and the presence of this breakage strongly predicts a poor clinical outcome. We assessed the possibility of differentiation-inducing therapy for acute leukaemias with chromosomal translocations involving 11q23. Among the cell lines with MLL translocations that we examined, KOCL48 and KOPN-1 cells were induced to differentiate into granulocytes by all-trans retinoic acid (ATRA) or into monocytes by 1alpha,25-dihydroxyvitamin D3 (VD3). These cells expressed p16 mRNA before treatment with 5-aza-2'-deoxycytidine (5-AZA), an inhibitor of DNA methylation. On the other hand, differentiation was not induced in SN-1, KOCL33, KOCL51 or KOCL44 cells by ATRA or VD3, and these cells did not express mRNA of this gene. However, these cells were effectively induced to differentiate by ATRA or VD3 in the presence of 5-AZA, and concomitantly exhibited p16 gene expression, suggesting an association between DNA demethylation and restoration of sensitivity to differentiation-inducing activity of ATRA or VD3 in leukaemia cells with MLL abnormalities. Based on these findings, combined treatment with ATRA or VD3 plus 5-AZA may be clinically useful in therapy for acute leukaemia with MLL abnormalities.

A variant form of CD44 that has additional amino acids in the common protein backbone (CD44-v6) seems to play a role in the metastasis of malignancies. We measured soluble CD44-v6 (sCD44-v6) by ELISA in 201 patients with malignant lymphoma. The sCD44-v6 level was significantly elevated in patients with non-Hodgkin's lymphoma (NHL) (n = 184). The sCD44-v6 level was correlated significantly with the standard sCD44 and soluble interleukin-2 receptor levels, but only weakly with serum lactate dehydrogenase (LDH). In 149 patients with aggressive NHL, the sCD44-v6 level was elevated in the subgroups with a high LDH level, stage III/IV disease, T-cell lymphoma, and high-intermediate or high risk group as identified by the International Prognostic Index (IPI). When the sCD44-v6 level wasor = 800 ng/ml the overall survival rate was significantly decreased (p = 0.0001). In the low + low-intermediate risk group (IPI) both overall survival rates (log-rank p = 0.0005, Wilcoxon p =0.002) were significantly decreased when the sCD44-v6 level wasor = 800 ng/ml. In multivariate analysis, sCD44-v6 was shown to be independent of the five prognostic factors in the IPI (age, performance status, number of extranodal sites, Ann Arbor stage and LDH level), so it may be useful for predicting the outcome of aggressive NHL.

We conducted a multi-institutional collaborative study to examine the usefulness and safety of third-generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony-stimulating factor (G-CSF) in the treatment of aggressive non-Hodgkin's lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low-intermediate, high-intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low-intermediate-risk cases, 13 high-intermediate-risk cases and 2 high-risk cases. Although all 24 patients were originally enrolled in the study, one adult T-cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low-intermediate-risk cases (89%) and 12 were either high-intermediate- or high-risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2-yr survival rate was 91.3%, and the 2-yr disease-free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%). CyclOBEAP therapy has been associated with a high remission rate for aggressive NHL. When combined with G-CSF, a high relative dose intensity was maintained for each drug administered (0.94-0.97). Furthermore, although the observation period was short, both the survival rate and disease-free survival rate were good. Hence, we concluded that there were no problems associated with the procedure in terms of safety.

The MLL gene is fused with the cAMP-responsive element binding protein-binding protein (CBP) gene in t(11;16)(q23;p13), which has been reported to be associated with therapy-related acute leukemia. We established a novel myeloid cell line, SN-1, from a patient with T-cell acute lymphoblastic leukemia with t(11;16)(q23;p13) having in-frame MLL-CBP fusion transcripts. The majority of the SN-1 cells were positive for myeloperoxidase when examined using an electron microscope and expressed CD13, CD33, CD56, and HLA-DR antigens, but not CD7, CD10, CD19, CD34, or CD41 antigens, suggesting that these cells are of myeloid origin. SN-1 cells underwent functional and morphological differentiation when treated with actinomycin D or sodium butyrate, but not with all-trans-retinoic acid (ATRA) or 1alpha,25-dihydroxyvitamin D3 (VD3). Exposure of SN-1 cells to ATRA hardly affected cell growth and differentiation, whereas the growth of HL-60 and NB4 cells treated with ATRA was effectively inhibited, and differentiation into mature granulocytes was induced. SN-1 cells were relatively insensitive to VD3 with respect to inhibiting the cell growth and inducing the ability to reduce nitroblue tetrazolium, lysozyme activity, and morphological differentiation, although the expression of CD11b was slightly induced by VD3. These results suggest that the cell line was impaired in the signal transduction systems of ATRA and VD3. This cell line should be useful for the study of the role of CBP as a transcriptional regulator in leukemia differentiation and for the functional analysis of the MLL-CBP fusion gene, which will provide new insights into leukemogenesis caused by 11q23 translocations.

The outcome of patients with non-Hodgkin's lymphoma has been improved by current approaches to treatment. Nevertheless, many patients either do not have a complete remission or ultimately relapse. To identify such patients, it is important to be able to predict the outcome. We previously found that the differentiation inhibitory factor/nm23 was correlated with the prognosis of acute myeloid leukemia. To examine the prognostic effect of nm23 on non-Hodgkin's lymphoma, we established an enzyme-linked immunosorbent assay procedure to determine nm23-H1 protein levels in plasma and assessed the association of this protein level with the response to chemotherapy, overall survival, and progression-free survival in patients with aggressive non-Hodgkin's lymphoma. The plasma concentration of nm23-H1 was significantly higher in patients with malignant lymphoma than in normal controls, especially in aggressive non-Hodgkin's lymphoma. The complete remission rate in patients with higher nm23-H1 levels was significantly worse than that in patients with lower nm23-H1 levels. Overall survival and progression-free survival were also lower in patients with higher nm23-H1 levels than in those with lower levels. The 3-year survival rates in patients with low and high nm23-H1 levels were 79.5% and 6. 7% (P =.0001). A multivariate analysis of prognostic factors showed that the plasma nm23-H1 level was independently associated with the survival and progression-free survival. An elevated plasma nm23-H1 concentration predicts a poor outcome of advanced non-Hodgkin's lymphoma. Therefore, nm23-H1 in plasma may be useful for identifying a distinct group of patients at very high risk.

Biweekly THP-COPBLM including pirarubicin (THP), which is thought to be less toxic than doxorubicin, was used to treat non-Hodgkin's lymphoma (NHL) and the remission rate and adverse events were studied in 42 patients younger than 69 years. Complete remission (CR) was achieved in 37 patients (88.1%) and partial remission in five (11.9%). Classified by international prognostic index, CR was achieved in 16 out of 17 low-intermediate-risk patients, 14 out of 16 high-intermediate-risk patients and seven out of nine high-risk patients. The 3-year survival rate was 72.1% and the 3-year event-free survival rate was 58%. Grade 3 or higher adverse events included granulocytopenia in 39 patients (92.9%) and thrombocytopenia in seven (16.7%). The biweekly THP-COPBLM regimen appears useful for the treatment of aggressive intermediate- and high-grade NHL, and G-CSF made it possible to shorten the interval between courses of chemotherapy. Further studies regarding adverse events on organs, other than on bone marrow are required to improve the long-term results of combination therapy on NHL.

123I-metaiodobenzylguanidine (MIBG) myocardial single photon emission computed tomography (SPECT), 123I-beta-methyliodophenyl pentadecanoic acid (BMIPP) myocardial SPECT, and holter ECG recording were performed in patients with non-Hodgkin's lymphoma who underwent chemotherapy including pirarubicin (THP), in an attempt at early detection of cardiac toxicity from THP. Twenty-six patients with untreated non-Hodgkin's lymphoma who received THP-COPBLM therapy were studied. For THP-COPBLM therapy. THP was administered at a dose of 40 mg/m2 every 21 days and the total dose was 250 mg/m2 on average (40 approximately 400 mg/m2). 1) The washout rate (WR) correlated with the total THP dose, and was considered to be a useful index of cardiac sympathetic nervous dysfunction. 2) The left ventricular ejection fraction (LVEF) correlated negatively with the total dose of THP. 3) The total dose of THP showed a correlated positively with the extent score and severity score determined by BMIPP. 4) The WR correlated with the frequency of premature ventricular contraction. Animal studies have indicated that THP has less cardiac toxicity than doxorubicin, but the present study showed that cardiac toxicity occurred at a total THP dose of about 360 mg/m2 in elderly patients. Accordingly, when THP is used to treat elderly patients, multimodal evaluation of cardiac is necessary to detect cardiotoxicity and to determine the optimal dosage.

Primary non-Hodgkin's lymphoma (NHL) of bone is a rare disease, accounting for less than 1% of all NHL cases and 3-5% of all extranodal lymphoma cases. Of 512 NHL patients treated at our department, 9 patients (1.8%, median age of 54 years) had primary NHL of bone. The disease was histologically of the diffuse type in all a patient, and of the large cell type in 6. The disease was at stage 1 in 8 patients and stage II in 1. The patients all received radiotherapy of 30-40 Gy following either the CHOP or COP-BLAM chemotherapy regimens. Treatment achieved complete remission in 8 patients. Six patients still alive (median follow-up: 63 months). It has been reported that survival is longer for patients treated with a combination of chemotherapy and radiotherapy than those, treated with radiotherapy alone. Consequently, we conclude that the standard treatment course for primary NHL of bone should be chemotherapy followed by radiotherapy.

A pilot study of high-dose biweekly cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy with granulocyte colony-stimulating factor support was carried out at 11 centers. Twenty-five patients with aggressive non-Hodgkin lymphoma under the age of 65 years old were registered. Lowest values of leukocytes and neutrophils scored grade 3 and 4 levels of Eastern Co-operative Oncology Group Toxicity Criteria in over 50% of the courses. Very rapid recovery of leukocytes and neutrophils was observed, and the duration of leukocytes under 1,000/microliter was less than 3 days in 72.2% of the courses. Leukocyte counts exceeded 2,000/microliter within 3 days in 69.1% of the courses. In most patients the hemoglobin and platelet count remained at grade 1 or 2 levels. Fever was seen in 15 out of 110 courses. In two-thirds of the 15 courses, fever disappeared within 3 days. Thus, administration of the CHOP protocol at biweekly intervals was feasible in 76.5% of the courses. Of 22 evaluable patients, there were 11 complete (CR) and 9 partial (PR) responses with an overall response rate of 90.9%. Among 13 high risk patients excluding 9 low and low-intermediate groups by International Prognostic Index, 7 CRs (53.8%) and 5 PRs (38.5%) were observed. This protocol is promising for aggressive chemotherapy of non-Hodgkin lymphoma.

Several neplanocin A analogs were synthesized and their growth-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.

Autoimmune hemolytic anemia (AIHA) complicated with non-Hodgkin's lymphoma (NHL) is not unusual. Two cases of NHL associated with cold agglutinin disease were reported. Case 1: A 38-year-old man had diffuse medium-sized cell NHL diagnosed by cervical lymph node biopsy. The Hb was 7.6 g/dl with a cold agglutinin titer of 32,768, and the IgM level was 890 mg/dl (I-specific), so cold agglutinin disease (CAD) was suspected. After administration of COP-BLAM therapy, complete remission (CR) was achieved along with a decrease in the cold agglutinin titer and improvement of anemia. Case 2: A 68-year-old woman had follicular mixed NHL diagnosed by inguinal lymph node biopsy. The Hb was 8.2 g/dl with a cold agglutinin titer of 51,200, and an IgM level of 920 mg/dl (I specific), thus concurrent CAD was suspected. Biweekly COP-BLAM therapy was administered and CR was achieved along with a decrease in the cold agglutinin titer and improvement of her anemia. In both patients, the cold agglutinin titer decreased after CR was achieved suggesting that production of anti-erythrocyte autoantibody was due to disturbance of the antibody system by NHL.

This study investigated 72 patients (12.4%) with follicular lymphoma among 582 patients with non-Hodgkin's lymphoma admitted to our department. Treatment achieved complete remission (CR) in 83.3% of the follicular lymphoma patients, with an overall 5-year survival rate of 63.7%. The 5-year survival rate was 76.9% for the 60 patients who achieved CR, and this rate was significantly higher than that for patients who achieved only partial remission (PR) (p0.01). The 5-year survival rate was 40% with the CHOP regimen and 74.3% with the COP-BLAM regimen. The 3-year survival rate for biweekly COP-BLAM was 88.4%. The 5-year disease free survival rate for patients who achieved CR was 80.5%. The rate reached a plateau after 42 months, and the same survival was maintained for more than 10 years. These results suggest that intensive chemotherapy is effective even against follicular lymphoma. The 5-year survival rate for patients who achieved PR, suggesting the importance of the response to initial chemotherapy.

AML1 may play a role in growth and differentiation of cells along erythroid and/or megakaryocytic lineages, because a significant level of the AML1 gene is expressed in these cells. We overexpressed AML1a (without the transcription-activating domain) and AML1b (with the domain) proteins in K562 leukemia cells, which can be induced to differentiate into hemoglobin-producing cells and megakaryocytes. The AML1a-transfected K562 cells had a reduced capacity to differentiate in the presence of sodium n-butyrate but not in the presence of other inducers, such as hemin, 1-beta-D-arabinofuranosylcytosine, and herbimycin A. The AML1 antisense oligodeoxynucleotide but not the sense oligomer recovered its differentiation-inducing capacity in the presence of butyrate. On the other hand, AML1b conferred a similar differentiation-inducing capacity upon K562 cells transfected with vector alone. AML1a expression was associated with enhanced sensitivity to megakaryocytic differentiation induced by phorbol ester. These results provide evidence that AML1 proteins play a role in erythroid and megakaryocytic differentiation.

We studied the remission rate and adverse effects in THP-COPBLM therapy consisting of pirarubicin (THP), which is said to be less cardiotoxic than doxorubicin. Subjects were 21 non-Hodgkin's lymphoma (NHL) patients older than 70 years of age. Of 21 patients, complete remission (CR) was achieved in 16 patients (76.2%) and partial remission in 2 patients (9.5%). Classified by stages, CR was achieved in 5 out of 6 patients in stage II, 7 out of 8 in stage III and 4 out of 7 in stage IV. Two-year survival rate was 61.5%. Adverse effects were observed in 7 patients (33.3%) with grade 3 or above leukocytopenia, 2 (9.5%) with thrombocytopenia and 1 (4.8%) with gastrointestinal symptoms. However, no abnormality in EKG was found, and the left ventricular ejection fraction in echocardiography did not differ before and after therapy. One patient each developed pneumonia and sepsis when they had granulocytopenia. THP-COPBLM therapy seemed useful in treatment of elderly patients with NHL. There were few adverse effects such as gastrointestinal symptoms or cardiotoxicity. However, leukocytopenia was observed in many patients despite combined use of G-CSF, suggesting the dose and administration method of THP should be studied further.

In order to investigate myocardial lipid metabolism in patients receiving chemotherapy regimens containing adriamycin (ADR) for hematological malignancies, 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT was performed. Thirty-two patients with hematological malignancies received a mean total ADR dose of 245 mg/m2 (range: 0-550 mg/m2). A polar map based on data from 8 normal individuals was used to calculate the extent score (representing the area of decreased uptake) and the severity score (representing the severity of defects) in the patients given ADR. 1) There was a significant association between the total ADR dose and the extent and severity scores. 2) The left ventricular ejection fraction was significantly associated with the extent and severity scores. 3) The two scores were also significantly associated with the washout rate of 123I-metaiodobenzylguanidine (MIBG). These results suggest that 123I-BMIPP myocardial scintigraphy reflects dysfunction of the myocardial mitochondria and serves as a guide for determining whether administration of ADR should be discontinued or the dose reduced.

COP-BLAM chemotherapy with concomitant G-CSF was performed on patients 65 or older with non-Hodgkin's lymphoma (NHL), and cardiac sympathetic disorders due to the chemotherapeutic agents were studied using 123I-MIBG (metaiodobenzylguanidine) myocardial SPECT (single photon emission CT). The results showed no correlation between the ejection fraction due to echocardiography and the total dose of adriamycin (ADR). However, there was a positive correlation between the total dose of ADR and the washout rate, and the possibility of cardiac sympathetic disorders caused by ADR was suggested.

In 59 patients with hematologic malignancy undergoing chemotherapy regimens including adriamycin (ADR), myocardial imaging was performed by SPECT with 123I-metaiodobenzylguanidine (MIBG) to detect cardiac sympathetic nerve abnormalities. SPECT imaging was performed 20 min and 4 hr after intravenous injection of 123I-MIBG, and the washout rate (WR) for the entire left ventricle was calculated. Then the relationship of the WR to the total dose of ADR, the left ventricular ejection fraction, and the frequency of arrhythmias was evaluated. It was found that the WR was related to the total dose of ADR, suggesting that it is a useful parameter for cardiac sympathetic nerve damage. As the WR increased, the frequency of ventricular arrhythmias also increased. The WR was usually normalized 3-6 months after the discontinuation of ADR. In patients with a WRor = 50%, however, prolonged follow-up was required. In conclusion, the WR on 123I-MIBG myocardial SPECT scans may be useful as a parameter for predicting cardiac toxicity requiring the discontinuation of ADR or dose reduction.

We studied whether adriamycin(ADM)-induced myocardial disorder in rats is advanced when recombinant human granulocyte colony-stimulating factor (rhG-CSF) is administered. Rats were divided into three groups (15 rats/group), i.e. the ADM group, the ADM+rhG-CSF group, and the vehicle-treated control group. ADM (2 mg/kg, i.p.) was administered for the first 2 days in each cycle and 10 days of administration of rhG-CSF (50 micrograms/kg, s.c.) was started two days after the second dose of ADM was given in each cycle. The dosing cycle was repeated 3 times. One day after the last dose, the following parameters were analyzed: peripheral blood and bone marrow cells, electrocardiogram (ECG) and histopathological findings. Four hours after intravenous administration of 125I-metaiodobenzylguanidine (125I-MIBG), accumulation of 125I-MIBG in some organs and findings from autoradiography (ARG) of the heart were examined. ECG revealed an extended ventricular activation (VAT) time in the ADM and ADM+rhG-CSF groups. In histopathological analysis, vacuolar degeneration of the myocardium was observed in both the ADM and ADM+rhG-CSF groups. The degree of change was the same for both groups. The accumulation of 125I-MIBG in the heart was lower in both the ADM and ADM+rhG-CSF groups than in the control group. The same tendency was observed in ARG, but the difference between the ADM group and the ADM+rhG-CSF group was not significant. These results suggest that administration of rhG-CSF at the standard clinical dose does not aggravate ADM-induced myocardial disorder. However, because this disorder may be more clearly manifested by treatment with higher doses of ADM, it is necessary to conduct further studies on the methods of dosing and administration.

COP-BLAM therapy with concomitant G-CSF was performed in patients 65 years of age of older with non-Hodgkin's lymphoma (NHL) and the therapeutic effects and its adverse effects were compared with those in a group not given G-CSF concomitantly. The subjects were 64 patients with NHL, divided into 36 in the G-CSF group and 28 in the non-G-CSF group. In the G-CSF group, complete remission (CR) was achieved in 88.9% and the efficacy rate was 94.5%. In the non-G-CSF group, 89.3% achieved CR, and there was no significant difference between the G-CSF and non-G-CSF groups. The survival time and duration of remission also showed no significant differences between the G-CSF and non-G-CSF groups. The frequency of granulocytopenia as an adverse effects was significantly reduced in the G-CSF group, but the other adverse effects showed no intergroup differences. The occurrence rates of fever of at least 37.5 degrees C and documented infection were significantly less in the G-CSF group. These results indicate that COP-BLAM therapy with concomitant G-CSF achieved a high remission rate, showed few severe adverse effects, especially infections, and can be safely performed in elderly patients.

G-CSF was used concomitantly with the COP-BLAM regimen, and its therapeutic results and adverse effects were evaluated. A total of 104 patients with untreated non-Hodgkin's lymphoma (NHL), including 22 in stage II, 52 in stage III and 30 in stage IV. Seventy five patients had diffuse large cell type, 18 diffuse medium cell type, and 11 diffuse mixed cell type. The treatment consisted of the COP-BLAM regimen based on the method of Laurence et al., was performed every 3 weeks. Complete remission was achieved in 98 out of 104 patients (94.2%), and the 4-year survival rate was 82.4%, while at the time of evaluation the median observation period was 26 months. The survival time was significantly prolonged in patients with low LDH values, B-cells, stage II or low CRP values. The COP-BLAM regimen with concomitant G-CSF administration achieved a high remission rate and reduced the frequency of infections. Almost all of the patients could be treated in 21-day cycle and this appeared to be effective for treatment with increased dose intensity.

Combination chemotherapy regimens using multiple agents have been reported to produce long term survival in patients with non-Hodgkin's lymphoma (NHL). However, the adverse effects of those regimens, particularly pulmonary complications, have resulted in fatalities. We measured P-III-P and type IV collagen-7S level in the serum and BALF of 23 previously untreated NHL patients who underwent COP-BLAM III chemotherapy in which a high dose of bleomycin (BLM) was used, and studied the relationship between those parameters and the pulmonary functions in those patients. The parameters and pulmonary function were measured before the first course and after the completion of the fourth course of chemotherapy. As for pulmonary function, chemotherapy produced an increment of %DLCO value but no change in PaO2, %VC, and %FEV1.0. While serum P-III-P levels remained unchanged, P-III-P levels in BALF slightly decreased after the chemotherapy. Type IV collagen-7S levels both in serum and BALF showed no change after the chemotherapy. Serum P-III-P levels after the chemotherapy were significantly correlated with both total cell counts and lymphocyte counts in the BALF. But there was no correlation between serum P-III-P levels and %DLCO. Mild and early-Stage fibrosis was observed in the lungs of the patients who were treated with COP-BLAM III. Pulmonary adverse effects are not likely to be associated with the total administered dose of BLM, but are associated with individual susceptibility to BLM toxicity. Our results suggest that the chemotherapy should be discontinued or the dose of BLM should be reduced if the P-III-P level in BALF increases.

In 29 patients who had been administrated adriamycin (ADR) for the treatment of hematopoietic malignancies, myocardial SPECT was performed 20 minutes and 4 hours after an intravenous dose of 123I-metaiodobenzylguanidine (MIBG). Findings of the myocardial SPECT were compared with the total dose of ADR, ejection fraction (EF) and left ventricular wall motion, as assessed by ultrasound echocardiography. The mean total dose of ADR was 329.3 mg/m2 (range, 150-550 mg/m2). 1) Although the cardiac function was normal, the washout rate (WR) of MIBG was high in 75% of the patients whose MIBG myocardial SPECT showed abnormality on ADR, suggesting the presence of adrenergic nerve disorder. 2) The total dose of ADR was significantly correlated with WR of MIBG (p0.001). Consequently, WR of MIBG may be an index which reflects adrenergic nerve disorder in the myocardium earlier than EF. 3) It was suggested that adrenergic nerve disorder was involved in pathogenesis of myocardial complications associated with ADR administration. In summary, MIBG myocardial SPECT could be a useful test for determining a dosage regimen of ADR therapy of individual patients.

The clinical effects of COP-BLAM III combination chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF) were examined in 60 patients with intermediate or high-grade non-Hodgkin's lymphoma (NHL). The patients consisted of 37 men and 23 women with a median age of 53 years. The modified COP-BLAM III regimen based on the method of Boyd et al. consisted of six cycles of 6 weeks duration each. The complete remission rate for all patients was 83.3% (50 of 60 patients). With the median observation duration of 47.5 months, the overall median survival time for all patients was 86 months or more. The disease-free survival rate for the 50 CR patients was 88.2% at 86 months. The incidence of infections was significantly reduced by the concomitant use of rhG-CSF. The most common adverse effect was neutropenia (or = 1000/microliters). The percent diffusing capacity for carbon monoxide in the lung (%DLCO) was reduced in 12 of the 60 patients (20.0%). We conclude that COP-BLAM III is a useful regimen for intermediate and high-grade NHL. However, caution is required since some elderly patients had reduced pulmonary function.

We report a case of Lennert's lymphoma complicated by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and autoimmune hemolytic anemia (AIHA). A 76-year-old female patient was admitted to our hospital because of cervical lymph node swelling. A diagnosis of Lennert's lymphoma was made by histological examination of the biopsied lymph node. She was also diagnosed as SIADH and AIHA. After the patient was treated with COP-BLAM therapy, lymph-adenopathy, SIADH and AIHA improved. However, lymph node swelling and hyponatremia became exacerbated again after the third course of COP-BLAM therapy. Then she was treated with IMV-triple P therapy. Eventually, she died of aspergillus pneumonia. The etiology of her SIADH was suggested to be an abnormal feedback mechanism of ADH secretion due to the infiltration of lymphoma cells into the diencephalic-hypophysial system.

Recently, the progress of chemotherapy has improved the clinical outcome of chemotherapy for hematopoietic malignancies considerably. However, the incidence of MRSA infections has increased in patients with hematopoietic malignancies, since preventive, multi-drug administration of antibiotics is frequently used in these patients. Moreover, patients with hematopoietic malignancies complicated by MRSA pneumonia have a poor prognosis. We examined lymphocyte subpopulations in bronchoalveolar lavage fluid (BALF) in MRSA pneumonia-complicated patients with hematopoietic malignancies and studied their relationship with the clinical features. We also discuss the cause of their poor prognosis. Of 223 patients with hematopoietic malignancies, 18 (8.1%) were complicated by MRSA pneumonia. Many of those patients had lymphoid malignancies. MRSA pneumonia occurred when neutrophil count was decreased. Most patients had been treated with chemotherapy containing anticancer drugs or with corticosteroid therapy. They had also been treated with third generation cefem antibiotics. We studied lymphocyte subsets in BALF in MRSA pneumonia-complicated patients with non-Hodgkin's lymphoma (NHL) and observed the local changes of the pulmonary immunological system due to NHL itself and due to anti-lymphoma chemotherapy. Our findings suggest the possibility that these immunological changes may play a role in the susceptibility to MRSA pneumonia.

ACVP-16 chemotherapy combined with recombinant granulocyte-colony stimulating factor (rG-CSF) was carried out on patients with malignant lymphoma which were recurrent or resistant to chemotherapy including adriamycin. Twenty patients with non-Hodgkin's lymphoma, 11 men and 9 women, with a median age of 54 years, were entered in this study. Fourteen patients had diffuse large cell lymphoma, 4 diffuse medium, and 2 diffuse mixed. The previous treatments for these patients were COP-BLAM, IMV-triple P and COP-BLAM III. The ACVP-16 regimen included ara-C at 100 mg/m2 i.v. on day 1 to 5, CBDCA at 250 mg/m2 i.v. on day 1, and VP-16 at 70 mg/m2 i.v. on day 1 to 3. Subcutaneous administration of rG-CSF at 2 micrograms/kg was started on day 7. Since complete remission was achieved in 7 patients (35%) and partial remission in 8 (40%), the total response rate was 75%. The median survival duration after the initiation of this therapy was 11 months for those who achieved CR and 4 months for those who achieved PR and those who had no response. Leukopenia (or = 1,000/microliters) and thrombocytopenia (or = 50,000/microliters) were observed in 15 (75%) and 12 (60%), respectively. We conclude that the ACVP-16 regimen is useful for the treatment of refractory or relapsed non-Hodgkin's lymphoma. However, the patients who are treated with this regimen should be carefully managed in order to avoid severe infection, because leukopenia was observed even when rG-CSF was administered.

Upper gastrointestinal examinations with simultaneous cardiorespiratory monitoring were performed in 39 older premature infants with persistent apnea. Swallowing incoordination was documented to be causatively related to persistent apnea in such infants, especially with feeding. Direct relationship between apnea and gastroesophageal reflux was not documented in this study.

A transferrin receptor was demonstrated in eight human established cell lines. Binding studies were conducted by measuring the amount of 125I-labeled diferric transferrin binding to these cultured cells indicated that the number of transferrin receptor per cell was distributed between 0.37 ± 0.22 × 105 and 4.96 ± 0.61 × 105, and association constant was between 1.91± 0.48 × 108 and 2.58 0.81 × 108M-1 by scatchard analysis. The binding site was specific for diferric transferrin, as studies showed that non-radioactive transferrin displaced labeled transferrin, while human albumin and IgG did not. In addition, only diferric transferrin could bind the transferrin receptors. However apotransferrin and two forms of monoferric transferrin did not show any significant binding to K-562 cells using 125I- labeled transferrins with different iron saturation. Moreover, number of transferrin receptor was markedly increased after s phase synclonization with thymidine and hydroxyurea. These experimental results clarified the specificity of transferrin receptors and suggested the possibility of transferrin receptors as a marker for cell proliferation.