The cellular proliferation kinetics of malignant lymphoma were investigated to obtain useful information for rational scheduling of chemotherapy. It is recommended to use intermittent combination chemotherapy covering the full generation time, although selection of treatment is also necessary on the basis of histologic type.
Combination chemotherapy with VEP, VENP, VQFP and VEPA was used as treatment. There were 33∼73% complete remissions with 67∼100% overall responses for previously untreated patients. The more favorable results of VENP therapy were seen in Hodgkin's disease. According to the LSG classification, the prognosis was proportionally poor to tumor cell size in diffuse lymphoma, while that of lymphoblastic and pleomorphic type was the worst and that of follicular lymphoma the best. The complete remission rate was lower for patients with T-cell type compared to non-T-cell type, and the median survival for T-cell type was only 6 months. A new effective protocol is needed for treatment of T-cell type lymphoma based on drug sensitivity studies.
In order to develope individualized predictive trials of anticancer drugs, we attempted to induce in vitro clonal growth of neoplastic lymphoid cells from fresh specimens of involved tissue, and conclude that further refinements of the assays are desirable before they can be applied to widespread clinical use.
OK-432, a streptococcus pyogenes preparation was assessed if it is useful to maintain complete remission achieved by chemotherapy. The remission duration was longer especially in Hodgkin's disease when complete responders received OK-432 alone instead of chemotherapy. When the in vitro response to PHA and NK activity by the lymphocytes were examined periodically along the clinical course, they recovered at complete remission and were enhanced by OK-432.

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One hundred and eighty-five patients with clinical stages I, II non-Hodgkin's lymphoma were treated between 1952 and 1982 with radiotherapy. Histological evaluation was reviewed blindly in one hundred and thirty-eight patiants by Rappaport's classification and LSG classification. Over 50% seven-year cumulative survival was obtained in stage I, II non-Hodgkin's lymphoma and the survical rate for diffevent classifications had shown significant characteristics of Japanese non-Hodgkin's lymphoma. Chemotherapy followed by radiotherapy which was completed in twenty seven cases gave good prognosis to the patients. Indications for combined radiotherapy/chemothevapy propram for non-Hodgkin's lymphoma patients is discussed.

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Our previous experiments revealed that streptococcal preparation, OK-432 and prostaglandin synthetase inhibitor, indomethacin have tumor inhibitory effects in mice inoculated with methylcholanthrene-induced sarcoma or Lewis lung carcinoma, especially when they were used in combination.
Indomethacin enhanced the lowered conA response of spleen cells from tumor-bearing mice both in vivo and in vitro.
The patients with malignant lymphoma had subnormal PHA responses in general which were frequently enhanced by indomethacin in vitro.
Evidences were shown that these effects of indomethacin were mediated through the inhibition of prostaglandin synthesis by plastic adherent suppressor cells.
The treatment of patients with a combined use of OK-432 and indomethacin resulted in the improvement of PHA response and the reduction of enhancing effect of indomethacin on PHA response. This combination immunotherapy appeared to have prolonged the period of remission duration when given simultaneously with maintenance chemotherapy.
The manipulation of suppressor mechanism together with the augmentation of effector mechanism will greatly enhance the effectiveness of immunotherapy.

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Five patients with advanced non-Hodgkin's lymphoma were treated with marrow-lethal doses of cyclophosphamide and total body irradiation (10 Gy) followed by the infusion of cryopreserved and rapidly-thawed autologous marrow. All five patients showed engraftment after autologous bone marrow transplantation (auto-BMT) and achieved complete remission (CR). Two patients of them have survived in treatment-free CR for more than 27 and 28 mo after transplantation as of in November, 1982. The other patient, however, developed relapse at 1.7, 13 and 14.5 mo posttransplant. There was no treatment-related death, although there were some tolerable complications.
Two patients with leukemic non-Hodgkin's lymphoma were treated with allogeneic bone marrow transplantation (allo-BMT) from HLA-identical siblings. They achieved CR but were died of interstitial pneumonia at 3.5 and 11 mo posttransplant, respectively.
From above-mentioned data it may be concluded that since auto-BMT is able to rescue marrow aplasia caused by marrow lethal therapy, a now protocol of therapy enough to eradicate tumor cells and also a proper method to precisely depict tumor invasion to the marrow should be settled in order to prevent posttransplant relapse. To patients with leukemic or advanced lymphoma an allo-BMT might be worthy of applying, if a HLA-identical sibling is found.

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We investigated in vitro anti-cancer drug sensitivity of seven long-term cultured cell lines established from human malignant lymphoma patients and peripheral blood mononuclear cells (PBL) from healthy donors. Anti-cancer drugs used in this experiment are adriamycin, cytosin arabinoside, daunomycin, vincristin, cyclophosphamide, methotrexate, dexamethason and d-mannosamine.
The effects of drugs on cultured cells and PBL were estimated by inhibition of DNA synthesis by ³H-TdR pulse-labelling and cell killing by trypan blue.
These cell lines and PBL have different sensitivities to various anti-cancer drugs. No similar drug sensitive profiles was observed among the cell lines tested.
These results may suggest the difficulty as well as the importance of combinations of drugs in chemotherapy of human malignant lymphomas.

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Studies were undertaken whether lymphoma and leukemia cells isolated from patients would be lysed by autologous and allogeneic interferon (IFN)-activated peripheral blood mononuclear cells (PBMC). PBMC from healthy donors and from patients were cultured with and without 500∼3,500 IU/ml of human fibroblast IFN for 24 hr and then their cytotoxic activity was assayed by a 5-hr ⁵¹Cr-release test. The results are as follows. Both lymphoma and leukemia cells were readily lysed by 500 U/ml IFN-activated normal donors' PBMC, whereas higher concentrations of IFN were reguired to enhance lytic activity of patients' PBMC against autologous tumor cells. Based on the results that lytic activity of the normal donor's PBMC was significantly suppressed by the addition of patients' PBMC, it was suggested that patients had suppressor cells which could inhibit either the lytic process of cytotoxic effector cells or the induction of effector cells with IFN.

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Cytotoxic activity of periperal blood mononuclear cells (PBMN) against K-562 cell line (NK activity) and autologous tumor cells (Autologous lymphocyte cytotoxicity) prepared from biopsied lymph node was examined in patients with malignant lymphoma.
The results are summarized as follows.
I (1) Cytotoxic activity of PB-MN against allogeneic K-562 cell line (NK activity) in 19 cases of malignant lymphoma was reduced compared with that of in normal subjects.
(2) Monocyte counts did not correlate with NK activity.
(3) The correlation between NK activity and stage of lymphoma was not clear in this study.
II (1) Autologous lymphocyte cytotoxicity (ALC) against own fresh lymphoma cells was almost absent in 9 patients as same as that in cases of chronic lymphadenitis.
(2) Cytotoxic activity of PB-MN from normal subjects against patients' lymphoma cells was also proved to be almost absent.
(3) In vitro treatment of effector cells with several immunomodulators resulted in no subsequent increase in their ALC activity, except for a slight augmentation following incubation with OK-432.
(4) In vitro treatment of target cells with same kind of immunomodulators brought about no increase of susceptibility to ALC nor decrease of viability of the target.
III The relation between NK and ALC activities and the reasons why the ALC remains at extremely low levels were not clarified. Adherent cell suppression for NK and ALC activities was not demonstrated in this study.
Further experiments are indicated to find interrelationships between malignant cell and immunocytes in this disease.

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Analysis of malignant lymphomas was performed by means of lymphocyte kinetic studies using In-III-oxine labeled autologous lymphocytes.
There were good relationships between recovery, half time of second component of disappearance curve and clinical stage of malignant lymphoma. The lower recovery and shortened half time were demonstrated together with the progress of clinical stage, however, blood lymphocyte pool (BLP) and recirculating lymphocyte pool (RLP) did not correlate with the clinical stage. In both T and B cell type of malignant lymphoma, smaller BLP was evident. RLP was normal in T cell type and smaller in B cell type of malignant lymphoma.
Organ distribution with gammer camera showed that lymph nodes were visualized in T cell type, but not in B cell type. These phenomenon suggested that recirculation of lymphocytes was more disturbed in B cell type than T cell type.
With the induction to complete remission by chemotherapy, recovery and half time normalized but remained lower in cases of incomplete remission. It was discussed that lymphocyte kinetic studies were valuable in the analysis of pathophysiology and therapeutic effects in malignant lymphoma.

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We investigated that such methods as (1) flow cytometric analysis of the subpopulation of peripheral lymphocytes by application of various monoclonal antibodies, (2) 0° 90° Light Scattering of cells in lymph nodes, peripheral leukocytes and bone marrow blood cells, (3) cell cycle analysis based on DNA histogram obtained cells present in lymph nodes stained with propidium iodide, and (4) cytofluorogram (CFG) of peripheral leukocytes, are useful to analyse the pathophysiology of malignant lymphoma.
Then we investigated the pathophysiology of malignant lymphoma in 32 patients using CFG of peripheral leukocytes and obtained the following conclusions.
1. CFGs of peripheral leukocytes in many malignant lymphomas revealed characteristic patterns different from those in controls even when there was no changes in routine blood check.
2. Abnormal CFG pattern in non-Hodgkin's lymphoma did not correlate to the histological classification of the disease, but seemed to correlate to the staging. However, abnormalities of CFG pattern were noted more frequently at stage III than at stage IV.
3. Prognosis of non-Hodgikin's lymphoma tended to correlate to CFG pattern obtained before treatment.
4. Remission and relapse of non-Hodgikin's lymphoma was related to changes in CFG pattern. CFG is therefore considered to be useful to observe the course of malignant lymphoma, especially that of extranodal-type.

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Clinical aspects of 71 patients with non-Hodgkin's lymphoma, including 51 Japanese and 20 American patients, were compared with the karyotypic features. A 14q+marker chromosome (14q32 translocation) was found in 25 of 43 patients with non-T cell lymphoma. In terms of survival, a significant difference was not noted betwen the two groups of 14q+positive and negative patients. Donor chromomes of a 14q32 translocation, which were identified in the 23 patients, were variable. However, a 8; 14 translocation [t(8; 14) (q24; q32)] was found in 8 patients with diffuse lymphoma, including 2 patients with Burkitt type lymphoma, and in one patient with nodular lymphoma, and a 14; 18 translocation [t(14; 18) (q32; q21)] was observed in 6 patients with nodular lymphoma and in one patient with diffuse lymphoma. Prognosis in these patients with t(8; 14), who had also partial trisomy for 1q, was extremely poor, because the clinical conversion of extranodal metastasis occured at the earlier disease phase, irrespective of clinical stage and histological diagnosis. incontrast the patients with t(14; 18) showed far better prognosis. Twenty-eight patients with adult T-cell leukemia and lymphoma (ATLL) did not have any chromosome changes peculiar for the disease entity, although a 14q+ marker chromosome was observed in five patients, including one patient with a Dq+ chromosome. In these patients with ATLL, those whose tumor was composed of clonally abnormal cells survived significantly shorter than those who had a majority of cells with a normal karyotype.
These findings suggest that in non-T cell lymphoma which has been primarily marked with a 14 q32 translocation, clinical aspects of the patients depend upon the donor chromosome and the following karyotypic evolution, and that prognosis even in patients with ATLL of a high grade malignancy could be correlated with chromosome changes.

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The clinical and pathophysiological implications of ferritin dynamics in terms of circulating ferritin secreting cells (FSC) were evaluated in patients with various hematological malignancies using a reverse hemolytic plaque assay.
The number of FSC contained in circulating monocytes and lymphocytes were greatly increased in patients with malignant lymphoma. The increase in the number of FSC was more prominent in patients with advanced disease, whereas it was less prominent in those in early stages or in complete remission following adequate chemotherapy.
The enumeration of FSC in patients with malignant lymphoma seems to help us evaluate the response to treatment.

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In this paper, clinical characteristics of each subgroups of lymphoma, and correlation between several parameters and clinical stage or prognosis were investigated in 67 cases (Hodgkin's disease; 17 cases, T cell lymphoma; 16 cases, non T lymphoma; 34 cases).
The results were as follows:
1) The leukemic manifestation was observed in 7.7% of the patients with Hodgkin's disease, in 43.8% of the patients with T-cell lymphoma, and in 12.1% of the patients with non T cell lymphoma.
2) The bone-marrow infiltration was noted in 62.5% of the patients with Hodgkin's disease and hepatic infiltration in 30.8%. The bone-marrew infiltration was noted in 50% of the patients with T cell lymphoma and hepatic infiltration in 30.8% and cutaneous infiltration in 25%. The bone-marrow infiltration was noted in 60.9% of the patients with non T cell lymphoma, hepatic infiltration in 36.7% and infiltration at the digestive tract in 42%. Immunoabnormality was observed in the patients with non T cell lymphoma (especially B cell lymphoma): Hyper-γ-globulinemia was noted in 22% of the patients, antinuclear antibody positive reaction in 23% and cryoglobulin-positive reaction in 31%.
3) Platelet counts were reduced in the terminal stage in many patients, indicating that the presence of bone-marrow infiltration in most cases.
4) Of 20 patients with high titer of serum alkaline phosphatase, 14 (70%) had the liver infiltration.
5) Serum ferritin, serum β₂-microglobulin and LDH were good parameters reflecting all clinical stages. However, as compared with ferritin, LDH showed higher incidence of normalization in the stage of non-remission. Reversely, β₂-microglobulin showed higher abnormal values in the stage of remission. Also, in renal disturbances, β₂-microglobulin was improper as a parameter.
6) PPD-skin reaction and PHA blast transformaton rate were both good parameters reflecting all clinical courses and stages. PHA rate before treatment was a good prarmeter for predicting the prognosis. The remission rate was high in patients with normal levels and was low in patients with low, or death occurred in the early stage in many patients with low levels. PPD skin reaction was negative in CS III stage and was positive in the remmision stage. At the time of relapse, and at the terminal stage, the reaction was again negative.
7) The level of the natural killer (NK) activities in malignant lymphomas tended to be lower than the normal control in all stages and increase in the remission period.

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The effect of certain disease parameters on response rate and survival time was evaluated in 47 patients with multiple myeloma treated with MIP therapy.
The results as follow:
1) In the response rate, older than 70 years old, female and poor risk factors such as anemia, hypercalcemia and hypoalbuminemia were associated with high response rates. IgA myeloma also showed higher response rate, in comparison with IgG myeloma.
2) In the survival time, older than 70 years old, male and poor risk factors such as hypoalbuminemia, elevated M-protein, hypercalcemia and extensive boone lesion were associated with short survival times. In addition, advanced stage showed significantly short survival times.
3) Greater degrees of M-protein reduction from chemotherapy were associated with longer survival times. Patiens in whom a marked M-protein reduction was rapid had longer remission and survival times than patients more slowly.
4) In the types of morphological myeloma proliferation, high respons rate on tumor forming type and long survival time on diffus proliferative type were obviously observed.

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This report consists of an analysis of 93 patients with multiple myeloma, registered between January 1973 and December 1981. Twenty-three received Melphalan alone or Melphalan and Prednisolone, fourty-six did Prednisolone together with sequential Melphalan and Ifosfamide (MIP therapy), and twenty-four did MIP plus Nitrosourea and Vincristine (MIP-NV). Although the relationship of M-protein and polyclonal immunoglobulin had been previously discussed in other reviews, clinical study on the disappearance of M-protein had not been conducted. Therefore, we discussed it here for the first time. The results were summarized as follows:
1. M-protein of myeloma patients disappeared during chemotherapy in eleven of 93 cases (11.8%), and the incidence of disappearance of M-protein (M (-)) was high in cases which received multi-combination chemotherapy and had plasmacytoma.
2. On IgG myeloma patients, cases of M (-) had low level of total protein and M-protein and high level of normal γ-globulin, IgA and IgM compared with those of non-disappearance of M-protein.
3. Median time for M-protein to disappear was 13 weeks, median duration of M (-) 59 weeks, and 50% survival from the treatment 30.0 months, which was longer than that of non-disappearance cases.
4. All cases of M (-) were overt myeloma at diagnosis and in these it was suggested that normal immunoglobulin producing clones were comparatively preserved coexist together with myeloma cell clones.

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Circulating immune complexes (CIC) in the sera of patients with hematologic disorders were detected by Clq deviation test (Clq DV), precipitin reaction of Clq in gel diffusion (Clq PR), and anti-antibody inhibition test (AAI).
The levels of CIC and the coincidence between results by Clq DV and AAI were high in sera of patients with acute myelogenous leukemia (AML) complicated with disseminated intravascular coagulation. The incidences of CIC in the sera of idiopathic thrombocytopenic purpura and malignant lymphoma were more than 50% by AAI, but no serum showed positivity by Clq DV or Clq PR. The incidences of CIC in the sera of patients with chronic myelogenous leukemia, chronic lymphocytic leukemia and autoimmune hemolytic anemia were about 50% by any method, but the coincidence between results by Clq DV and AAI was very low. The incidence and the levels of CIC were low by any method in sera of patients with multiple myeloma.
CIC levels detected by Clq DV showed a weak and negative correlation with survival times of patients with AML. No correlation was shown between CIC levels and clinical data of patients with other than AML.
These results suggest that it is necessary to detect CIC for diagnosis and evaluation of patients with hematologic disorders by several methods whose principles are different from each other.

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A 16-year-old girl was admitted to the Third Department of Internal Medicine, AKita University Hospital with the chief complaints of yellowish discoloration of the skin and easy fatigability. Physical examination revealed mild splenomegaly. Hemoglobin concentration was 9.7 g/dl, reticulocyte count 9.8%, serum total bilirubin 7.1 mg/dl, indirect bilirubin 5.6 mg/dl, and ⁵¹Cr-labeled red cell half life 5 days. In the peripheral blood there were many elliptocytes, and types III and according to the Günther's classification were 41.5 and 31.5%, respectively.
Increased Na flux and ATPase activity were proved in red cells of the patient. The diagnosis of hereditary elliptocytosis accompanied by hemolytic anemia was made. Splenectomy was performed on June 13, 1980, and jaundice and anemia were improved. In the family study, no other member showed elliptocytosis.

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A 41 year-old man was admitted in January, 1981 because of fever and anemia. The peripheral blood showed pancytopenia without blast cells. Teardrop-shaped erythrocytes were not found. Neither hepatosplenomegaly nor lymphadenopathy was detected. Bone marrow aspiration was unsuccessful, and biopsy showed myelofibrosis with hyperplasia of megakaryocytic series and hypoplasia of erythroblasts and granulocytes.
The patient was diagnosed to have acute myelofibrosis.
The course was rapid and the patient died in 7 months.
The postmortem examination showed myelofibrosis of the bone marrow, and infiltrative proliferation of atypical mononuclear cells which were naphthol-AS-D-chloroacetate esterase-negative and megakaryocytes in the liver, spleen and lymphnodes. These findings were consistent with megakaryoblastic leukemia figuring as acute myelofibrosis.

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This paper is concerned with a case of a 22-year-old woman in which ecchymoses caused by factor VIII inhibitor were developed on her arms and legs, 11 months after her first delivery of a normal boy.
There was no previous personal or family history of abnormal bleeding. She had received neither drugs nor blood transfusion.
On admission, factor VIII inhibitor activity was 2.3% and the titer of factor VIII inhibitor was 3.5 Bethesda units. Her chemical data of the blood were normal, and tests for antibodies, such as LE test, DNA test, microsome test, immunecomplex, RA test and thyroid test were negative.
The inhibitor was characterized as follows: it neutralized factor VIII activity rapidly at first and thereafter slowly with the prolonged incubation time, and it was eluted as an intermediate (7S) peak in gel filtration with Sephadex G-200, and neutralized with IgG or kappa antibody in neutralization tests.
By treatment with a combination of 6-mercaptopurine and prednisolone, the hemorrhagic symptoms were improved and the inhibitor disappeared after one month. Follow-up was continued as an out-patient for 18 months. She did not have any new bleeding episodes throughout the period and the inhibitor could not be demonstrated again.

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