Studies of cellular proliferation in human leukemia. I. Estimation of growth rates of leukemic and normal hematopoietic cells in two adults with acute leukemia given single injections of tritiated thymidine.

Two adults with rapidly progressive acute myeloblastic and myelomonoblastic leukemia were given single injections of tritiated thymidine, and measurements were made of the growth rates of their leukemic and normal hematopoietic cells by radioautographic methods. Although almost all leukemic blasts in both marrow and blood were metabolically active as shown by their ability to incorporate tritiated uridine and leucine in vitro, only 5.6% and 6.1% of the blasts in the marrow and even fewer in the blood incorporated tritiated thymidine. The mitotic indexes of the marrow blasts were 0.66% and 0.52%; no circulating blasts were dividing. The mean generation times of the actively proliferating blasts were estimated to be 49 and 83 hours. This cannot be equated with the doubling time of the total leukemic population as there is evidence that many blasts fail to continue dividing and die. The mean durations of the phases of the blasts' mitotic cycles were as follows: DNA synthesis (S) = 22 and 19 hours, premitosis (G(2)) = 3 hours, mitosis (M) = 0.47 and 0.62 hour (minimal estimates), and postmitosis (G(1)) = 24 and 61 hours. In both patients the maximal mean transit time of the blasts in the blood was 36 hours, and the minimal numbers of actively dividing blasts present were 1.6 and 2.6 x 10(9) per kg of body weight.Estimates were also made of the rates of proliferation and maturation of the residual normal erythrocytic and granulocytic cells in these two patients. Although total production was markedly diminished because of reduction in the number of normal elements, the relatively few remaining normal cells appeared to be dividing and maturing at rates that are about the same or only slightly slower than those found in normal subjects. We conclude that main reason leukemic blasts displace normal hematopoietic precursors in acute leukemia is that the blasts largely fail to differentiate. Many die but many others persist in the marrow and elsewhere as primitive cells and continue to proliferate. As the blasts accumulate, they gradually displace the normal hematopoietic cells, most of which continue their normal course of differentiation and leave the marrow as nondividing mature cells. It is not known why the over-all production of normal cells is not adequately increased to compensate for the anemia, granulocytopenia, and thrombocytopenia that develop, but apparently the leukemic cells somehow interfere with the proliferation or differentiation or both of normal stem cells.

Effect of pre-existing four hour coronary stenosis on ventricular arrhythmias during a subsequent 10 minute occlusion in dogs.

STUDY OBJECTIVES: The aim was to assess the effect of pre-existing coronary stenosis on ventricular arrhythmia during subsequent acute coronary occlusion. DESIGN: Dogs with a 4 h intact interval followed by a 10 min occlusion of left anterior descending coronary artery (group A) were compared for ventricular arrhythmias with dogs with a 4 h stenosis of the same artery followed by a 10 min occlusion (group B). Myocardial blood flow was measured in the ischaemic myocardium using the H2 gas clearance method to exclude dogs with good collateral flow (myocardial blood flow greater than 11.0 ml.min-1.100g-1). EXPERIMENTAL ANIMALS: 35 mongrel dogs of either sex, weight range 11-26 kg, were used in the experiments (group A, n = 17; group B, n = 18). After exclusion of dogs with good collateral circulation there were 11 dogs in group A (subgroup A1) and 12 dogs in group B (subgroup B1). MEASUREMENTS AND MAIN RESULTS: The incidence of ventricular fibrillation was lower in group B (pre-existing stenosis) than in group A during the 10 min occlusion, though there was no difference in numbers of ventricular premature beats. Maximum ST segment elevation and maximum conduction delay were less in group B than in group A, but myocardial blood flow did not differ during the 10 min occlusion. In the subgroups the incidence of both types of ventricular arrhythmia was lower in subgroup B1 during the 10 min occlusion, while the maximum ST segment elevation and maximum conduction delay were less, and myocardial blood flow was greater. CONCLUSIONS: Pre-existing 4 h coronary stenosis causes the development of collateral flow and reduces the incidence of ventricular arrhythmias during subsequent occlusion.

A mode of incipient growth in chemically induced signet ring cell carcinoma of the canine stomach.

A 31-month-old female mongrel dog was orally administered with 50 mg or 100 mg of N-nitrosobutylurea (NBU) in gelatin-capsule 3 times per week for 19 months with interposing periods of complete suspension. Thirty-four foci of signet ring cell carcinoma were found in the antral region of the stomach. The majority of the foci (31 foci) were early cancer, and the remaining foci were invasive cancer. In addition to these lesions, there was "a single gland cancer" in which a row of cancer cells was confined to a single gland. The whole gland was composed of two cell layers; the inner layer facing the lumen was normal gastric cells and the outer layer was atypical or neoplastic cells underlaid by the basement membrane. Mitosis was frequently observed on the bottom of the gland. Atypical or neoplastic cells seemed to mature gradually through a process of upward migration with increase in cytoplasmic Alcian blue-PAS and HID-AB positive mucin. Some of the cells rich in mucin moved into the lamina propria. The other cells remained in the flow of the regular cell renewal system of the normal gastric cells and reached the top of the gland. This observation revealed a mode of incipient gastric cancer growth, which starts and spreads within a single gland, before it invades the surrounding lamina propria.

[A case of central retinal vein occlusion forming the epiretinal membrane].

BACKGROUND: We encountered a patient with central retinal vein occlusion (CRVO) forming an epiretinal membrane (ERM) in a wide area. Generally formation of ERM is rare in CRVO. PATIENT AND METHODS: The patient was a 72-years-old female with ischemic CRVO in the right eye, who had undergone insufficient pan-retinal photocoagulation. Since ERM was formed in a wide area 7 months after the occurrence of CRVO, the patient underwent vitrectomy. RESULTS: Although the patient was elderly, the posterior vitreum had not been detached, and ERM was observed in a wide area from the disk of the optic nerve over the vascular arcade. Since the ERM strongly adhered to the retina, incision of the membrane with vitreous scissors was required. The membrane tissue collected during the operation showed few vascular and cellular components, and consisted of ERM extracellular matrices such as collagen. CONCLUSIONS: In this patient, however, it was probable that not only barrier dysfunction of retinal vessel endothelial cells caused by elevated pressure in the retinal vein and rapid retinal ischemia but also the anatomical feature of the undetached posterior vitreum was involved in the formation of the ERM.

[IgM myeloma without depression in serum IgG and IgA--a case report].

A 64-year-old woman with a monoclonal gammopathy was admitted to Nagoya National Hospital with the complaint of occasional hemoptysis. On examination, there was no hepatosplenomegaly or no lymphadenopathy. The hemoglobin was 10.1 g/dl; platelets 22.5 X 10(4)/microliters; white blood cells 4.9 X 10(3)/microliters, with 4% of atypical lymphocytes. Immunoglobulin analysis of the serum by immunodiffusion revealed an IgG of 1,459 mg/dl, an IgA of 219 mg/dl, and an IgM of 5,091 mg/dl. Serum viscosity was 4.9. Serum immunoelectrophoresis demonstrated atypical precipitant arcs reacting with mu and kappa antisera. Urine immunoelectrophoresis showed a positive reaction against kappa antiserum. Radiologic studies of the bones revealed generalized osteoporosis with multiple punched out lesions of the skull. Thirty percent of bone marrow nucleated cells was atypical plasma cells, the presence of which was verified by electron microscopy. Although they were positive mainly for cytoplasmic mu and kappa chains by immunoperoxidase studies, cells positive for gamma, alpha, or lambda chains were occasionally found, indicating that normal immunoglobulin synthesis was not suppressed in this case of IgM myeloma.

[Pure red cell aplasia with inhibitor to erythroid precursors in serum].

A patient with pure red cell aplasia (PRCA), who had the inhibitor to erythroid precursors in serum, is described. A 72-year-old female was referred to Nagoya National Hospital because of progressing anemia in April 1988. On admission, her hemoglobin was 4.8 g/dl, reticulocyte 0.8%, and bone marrow specimen contained only 1.2% erythroblast. On these bases, she was diagnosed as pure red cell aplasia. After small amount of blood was transfused, her hemoglobin and erythroblast in bone marrow (EBM) increased to 7.8 g/dl and 39.1%, respectively, and she was discharged. However, after a month, her hemoglobin dropped to 4.6 g/dl, reticulocyte to 0.1%, and EBM to 0%. Soon after corticosteroid therapy (prednisolone, 40 mg, daily) was started, a marked elevation of reticulocyte count was observed, and then her hemoglobin increased to 11.0 g/dl, and EBM to 31.6%. The reason for a transient spontaneous remission at the onset of her disease was occurred is unclear. The number of BFU-E in her bone marrow was within normal range, but it was suppressed significantly (65%) after the addition of her serum and the complement purified from rabbit plasma. This finding suggest the presence of inhibitor to erythroid precursors in her serum.

[So-called Ph1-negative chronic myelogenous leukemia with a mosaic pattern of trisomy 8 and normal karyotypes--report of 2 cases].

Two cases of Ph1-negative chronic myelogenous leukemia (CML) are described, they were 66-year-old female and 73-year-old male. Both patients shared all of the following features: presence of anemia, thrombocytopenia and leukocytosis with every stage of neutrophilic differentiation, hypercellular bone marrow with hyperplasia of the degranulated neutrophilic series, diminished neutrophilic alkaline phosphatase, elevated serum lysozyme and vitamin B12 level, mosaic pattern of trisomy 8 and normal karyotypes in chromosome analysis, and markedly increased number of CFU-GM. In addition, bcr rearrangement by Southern blot hybridization was not demonstrated in these patients. The diagnosis of chronic myelomonocytic leukemia was not verified, however, because of the absence of monocytosis in peripheral blood. The existence of so-called Ph1-negative CML like these two cases as a diagnostic entity must be further studied.

[Therapeutic treatment of Borrmann type 4 (scirrhous) gastric cancer-chemotherapy and histopathological studies].

Up to now, there has been no investigation documenting clearly the effectiveness of chemotherapy for Borrmann type 4 gastric cancer from a histopathological viewpoint. In this paper, we present a few representative cases of Borrmann type 4 gastric cancer in which microscopic examination revealed the therapeutic effectiveness (degradation of cancer cells) of neoadjuvant chemotherapy. Further, comparative studies will be needed to clarify the relationship between the assessed effectiveness of therapy by roentgenological and histopathological examination.

[Mitoxantrone and conventional-dose cytosine arabinoside for relapsed and refractory acute leukemia].

Fourteen patients with relapsed or refractory acute leukemia received combination chemotherapy of mitoxantrone 6 mg/m2/day intravenously for three to six days and cytosine arabinoside 60 mg/m2/day intravenously over 24 hours continuously for five to ten days. Complete remission was attained in six patients (42.9%) and partial response in two patients (14.3%). Six patients (42.9%) had resistant disease, and four patients (28.6%) died during the myelosuppressive phase. Of the patients achieving complete remission, four relapsed and other two continued complete remission up to 27.3 months. Median remission duration was approximately 10.6 months. No significant difference was found with regard to the efficacy of our regimen between AML and ALL. Hematological toxicity was no more severe than the prior cumulative chemotherapy. Major non-hematologic side effects were nausea and vomiting (71.4%), stomatitis (64.3%) and liver dysfunction (57.1%), which were moderate and manageable, while no cardiotoxicity was observed in any patient. In conclusion, the combination chemotherapy of mitoxantrone and conventional dose cytosine arabinoside is an effective salvage therapy in relapsed or refractory acute leukemia, and our regimen has possible utility as first-line chemotherapy in de novo acute leukemia also.

[Assessment of the combined effects of mitomycin C with alpha-interferon or gamma-interferon by the clonogenic assay technique].

The combined effects of Mitomycin C (MMC) with alpha-interferon (HLBI) or gamma-interferon (TRP-2), which have become attractive drugs for use as Biological Response Modifiers, were investigated using the human tumor clonogenic assay technique. Tumors in this study were five human tumor xenografts serially transplanted into nude mice (three gastric cancer, two colon cancer). When the survival fraction occurring with the combination was smaller than that obtained by multiplication of the survival fractions occurring with either drug alone, the combined effect was considered to be synergism. Four out of five xenografts (three gastric cancer, one colon cancer) showed synergistic effects for the combination of MMC with alpha-interferon. Although two gastric cancer xenografts showed synergism for the combination of MMC with gamma-interferon, antagonistic effects were observed in one gastric cancer and one colon cancer xenograft.