In Europe and America there are a number of reports of leukemia occurring in two or more members of a family, as well as twins. Chronic lymphocytic leukemia is the most commonly found variety in these instances. Cases of chronic myeloid leukemia are extremely rare. Acute leukemia occupies an intermediate position.
In cooperation with Prof. Dr. Wakisaka, Dr. Yoneda and Dr. Uchino of the University of Kyoto, 29 instances of leukemia occurring in 2 members of the same family in Japan were collected by us. Eight of them have already been reported in literature. Of the 29 instances, 7 are a parent and a child, 11 are siblings, 2 are a grandparent and a grandchild, 6 are an uncle or aunt and a nephew or niece and 3 are cousins.
As lymphocytic leukemia is rare in Japan, myeloid leukemia is found most commonly in our familial cases. The acute form is observed about two times more frequently than the chronic form, indicating no significant difference from the recent trend in the form of myeloid leukemia in general in Japan.
The incidence of familial leukemia, as noted by earlier authors, differs from 9.1 per cent by Ardashnikov in 1937, 8.1 per cent by Videbaek in 1947, to 0.45 per cent by Guasch in 1954. In Japan the various values given are 0.4 per cent by Oota, 0.5 per cent by Wakisaka and 0.85 per cent by Shiraishi in 1958, 0.2 per cent in chronic leukemia and 0.3 per cent in acute leukemia by Komiya in 1959. It appears that the familial incidence of leukemia is very rare, at least in Japan.
More than 20 cases of congenital or fetal leukemia have been reported in Japan. Maternofetal transmission, however, has not been observed.
Recent reports have emphasized the possible biological significance of the simultaneous occurrence of acute leukemia and mongolism in children. In Japan, few reports of such cases have been described in literature, but no statistical data are yet available.
Spontaneous as well as induced leukemia in mice shows that heredity may be of importance in determining susceptibility to leukemia. Evidence for a familial occurrence of leukemia in the human subject, as yet, is not sufficiently strong to prove that heredity is concerned in the etiology of leukemia.
The presence of an hereditary factor in leukemia is certainly most suggestive in those instances in which multiple cases occurred in close relatives. Such families, as well as twins, however, have not yet been reported in Japan.

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Some comments on the progress of myelogenous leukemia are made in this paper.
I. From the follow-up studies of 14 cases of chronic myelogenous leukemia, it was proved that there were cases which did not show any remarkable increase of myeloblasts in the peripheral blood in spite of acute clinical exacerbation of the disease.
Even in acute myelogenous leukemia parallel relationship between the severity of the disease and the counts of the myeloblasts in the peripheral blood (sometimes in the bone marrow and other organs) is not always found.
It is well known that there are many cases which develope severe clinical manifestations and die in spite of obtaining good hematological remissions due to anti-leukemic drugs.
From this point of view, it seems that there is a factor, which aggravates the clinical progress of the leukemia, this factor may not be the leukemic cell, but some unknown factor which remains to be discovered.
II. If the chronic and acute myelogenous leukemia are the same disorders induced by the same etiological factors, the chronic myelogenous leukemia must be the forerunner of acute leukemia, because many cases of chronic myelogenous leukemia change to acute leukemia, but no case of acute leucemia changing to chronic leukemia has been reported.
For this reason, it seems to be obvious that the progress of myelogenous leukemia can be divided into three stages, i. e. non symptomatic, non acute and the acute stage. The non acute stage embraces almost all cases of chronic leukemia and some cases of acute leukemia. The acute stage involves almost all cases of acute leukemia and cases with acute exacerbation of chronic leucemia.
The fact that acute leukemia does not change to chronic leukemia and there is no lineal relationship between clinical severity and the blood picture, can not be explained without using such a theory.

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Im Tierexperiment kann man normalerweise bei fast allen verwendeten Tierspezies Leukämien finden. Bisherige experimentelle Untersuchungen über Zusammenhänge zwischen einer Bestrahlung und dem Auftreten von Leukämien wurden vorwiegend an Mäusen durchgeführt. Es zeigte sich, dass, wie auch andere Tiere, verschiedene Mäusestämme eine unterschiedliche Leukämieempfindlichkeit aufweisen.
Bereits 1930 beobachtete KREBS¹⁾ einen Anstieg der Leukämierate von Mäusen als Folge einer Ganzkörperbestrahlung. Dieser Anstieg betrug allerdings nur 2.9%. FURTH²⁾ sah 1936 nach einmaliger Bestrahlung der Tiere mit 200 bis 400 r einen 7-8 fachen Anstieg, UPTON³⁾ nach 110 bis 165 rad einen solchen auf 43% und COTTIER⁴⁾ nach einmaliger Bestrahlung mit 600 r einen 3 fachen Anstieg. Bei fraktionierter Bestrahlung fanden LORENZ⁵⁾ bis zu 8.8 rad pro Tag, er beobachtete einen Anstieg auf mehr als 50%, SPARGO⁶⁾ bei 8.8 rad pro Tag einen solchen von 1% auf 6% und KRÖNING⁷⁾ nach 5 mal 160 r einen Anstieg von 0 auf 83%.
Die Frage nach der Ätiologie der strahlenbedingten Leukämie kann heute ebensowenig beantwortet werden wie bei Leukämien aus anderen Ursachen. Zur Zeit liegen lediglich einige tierexperimentelle Beobachtungen vor, die Hinweise für experimentell verfolgenswerte Wege geben. Ein sehr interessantes und bedeutsames Problem ist dabei die Frage nach dem Vorliegen leukämogener Substanzen, im Vordergrund steht dabei die Untersuchung einer leukämogenen Wirkung von im Organismus vorhandener Metabolite.
Seit den Arbeiten von BÜNGELER⁸⁾ weiss man, dass das Indol, ebenso eine leukämogene Wirkung besitzt wie das Indikan. Andere Metabolite, insbesondere solche des Tryptophan-Stoffwechsels, erweisen sich ebenfalls leukämogen. Hier sind in erster Linie das 3-Hydroxykynurenin und die 3-Hydroxyanthranilsäure von Bedeutung.
Die Möglichkeit einer endogenen Erzeugung von Leukämien wirft die Frage auf, ob das Auftreten von Leukämien an Störungen des Tryptophanumsatzes und damit ganz allgemein der Proteine gebunden ist. In der Tat zeigen die Statistiken eine Parallelität zwischen der Häufigkeit von Leukämien und dem Steigen des Lebensstandards.
Nach STICH und EHRHART⁹⁾ kann z. B. die karzinogene Aktivität von 2-Acetylaminofluoren auf eine Verhinderung des weiteren Abbaus von 3-Hydroxyanthranilsäure und der damit verbundenen Kumulation von 3-Hydroxyanthranilsäure und von 3-Hydroxykynurenin zurückgeführt werden. Eigentlich wirksame Verbindungen wären das 3-Hydroxykynurenin und die 3-Hydroxyanthranilsäure, wobei durch die Gabe von 2-Acetylaminofluoren nach DUNNING und CURTIS¹⁰⁾ eine Blockierung des weiteren Abbaus von 3-Hydroxyanthranilsäure zu Chinolinsäure bzw. Nikotinsäure verursacht wird. Die 3-Hydroxyanthranilsäure konnte inzwischen auch durch EHRHART und Mitarb.¹¹⁾ im Tierversuch bei Mäusen als leukämogene Substanz nachgewiesen werden.
MUSAJO und Mitarb.¹²⁾, DALGLIESH und TEKMAN¹³⁾, MUSAJO, BENASSI und PARPAJOLA¹⁴⁾ sowie AURICCHIO und Mitarb.¹⁵⁾ stellten im Harn von leukämiekranken Patienten vor allem Kynurenin, 3-Hydroxykynurenin und verschiedene Derivate dieser Substanzen fest. Im Mäuseversuch führt ein Pyridoxinmangel zu Granulozytose und Lymphopenie und verringert die Überlebenszeit von Tieren mit Transplantations-Leukämien, die eine stärkere leukämische Leukozytose als normal ernährte leukämische Mäuse entwickelten (WEIR und MORNINGSTAR¹⁶⁾).
Auch die Ergebnisse von BECKMANN¹⁷⁾

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We have often reported that acute leukemia can clearly be classified into three types on the basis of morphological or functional characteristics of the movement of the blast cell. Clinically and hematologically, acute and chronic cases were comparatively studied of monocytic (18 acute, 5 subacute and 5 chronic cases) and lymphatic (18 acute and 5 chronic cases) leukemia out of 109 cases of leukemia.
Clinical symptoms: (a) Monocytic leukemia: The duration between onset and initial examination was 1.9 months for acute cases, 4.4 months for subacute cases, and 7.6 months for chronic cases on an average. Subacute or chronic cases show a less degree of anemia and lymphadenopathy but more frequent splenomegaly than acute cases. Fever and hemorrhagic tendency prove much less frequent and hepatomegaly in a less degree in chronic cases than acute and subacute cases. (b) Lymphatic leukemia: The duration between onset and initial examination was 1.7 months for acute cases, and 7.0 months for chronic cases on an average. Chronic cases show less fever, anemia and hemorrhagic tendency but more marked lymphadenopathy and splenomegaly than acute cases.
Hematological findings: Chronic cases generally show higher R. B. C., hemoglobin content and W. B. C. than acute cases, but there was little difference among acute, subacute and chronic cases of monocytic leukemia. The bone marrow cells showed almost the same number in all cases of the types studied, except for chronic cases of monocytic leukemia which showed a relatively low count. L/E ratio was generally very high for all cases except for chronic cases of monocytic leukemia which were within normal limits. The leukemic blast cells were much less in chronic cases than in acute cases. Occasionally it seemed rather difficult to differentiate successfully acute cases from subacute and chronic cases of monocytic and lymphatic leukemia on the basis of hematological changes observed by ordinary methods. The importance of observations of the movement of leukemic cells was stressed, being an influential aid in the differential diagnosis of acute and chronic cases of monocytic and lymphatic leukemia.

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Much have been discussed as to the presence or absence of acute lymphatic leukemia, but the final conclusion has not been established. And, incidence of acute lymphatic leukemias and monocytic leukemias has been contradictorily reported. This paper deals with the classification of acute leukemic cells in blood and bone marrow by means of cytochemical stainings. As the cytochemical stainings localized in neutrophilic granules, stable Nadi oxidase, peroxidase, DOPA oxidase, sudan black B and dithizone stainings were selected, and as the mitochondrial stainings, labile Nadi oxidase and succinic dehydrogenase. Amylophosphorylase, PAS stainings, acid and alkaline phosphatases, esterase and aminopeptidase were adopted as the cytoplasm stainings.
These observations revealed that myeloblastic, paramyeloblastic, monocytic and most of lymphoblastic leukemias are readily differentiated by these cytochemical stainings of acute leukemic cells.

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The factors influencing effects of chemotherapy were studied in 122 cases of acute myelogenous leukemia during the initial treatment. These factors are age, leukocyte level, percentages of leukemic cells in hemogram and myelogram, peroxidase reaction, mitochondrial arrangement and Auer body in leukemic cells.
According to the criteria we adapted for evaluation of chemotherapeutic effects, the definition of remission was established.
The remission rates were composed in the four chemotherapeutic groups which were conventional and lange doses of steroid hormone, 6 MP and combination of steroid hormone and 6 MP.
It was concluded that children were more effective than adults in every four agents, and that steroid hormone was effective in adult patients with low leukocyte level, low percentages of leukemic cells in hemogram, without positive leukemic cells for peroxidase reaction, without leukemic cells of mitochondrial arrangement of Simpson's type, and without Auer body in leukemic cells.
The effects of 6 MP were showed the approximately same patterns as steroid hormone in patients with low percentages of leukemic cells in hemogram and without Auer body in leukemic cells, but reverse pattern with mitochondrial arrangement of Simpson's type in leukemic cells and leukocyte level, and no relations with peroxidase reaction.
The combination therapy showed a beneficial effect rather uniformly despite the differences in these factors.

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The rarity of the initiation of acute leukemia with epistaxis due to a mediastinal tumor prompted the authors to describe this paper.
The patient was a 15 year-old boy, who was admitted as an emergency case with the complaints of epistaxis of three days' duration and dyspnea of one week's duration. About 3 weeks prior to admission he saw a doctor with a complaint of edematous face, but urinalysis showed nothing abnormal at that time.
Remarkable signs on admission: anemia, polypnea (26 per min.), low blood pressure, edema at face through neck, epistaxis, pathologic dullness at manubrium area (bilaterally 1-2 fingerbredths outer from the sternal rim), miliary petechia all over the body, and submandibular lymphnod enlargement in small-finger-tip size.
Laboratory data: As shown in Tables 1 and 2, accentuation of ESR, high value of GOT, positive occult blood in feces; in blood study, thrombopenia, prolonged bleeding time, and marked increase in WBC (39, 600) with a few promyelocytes (Photo. 1) and myelocytes. Bone marrow study (Table 2 and Photo. 2) showed hypercellularity and presence of dominant myeloblasts which had a marked variety in size and the nucleus. Chest x-ray (Fig. 1) showed a giant, upper mediastinal tumor. Thus it was apparent that this patient had acute myeloblastic leukemia accompanied by thrombopenia and mediastinal tumor, and epistaxis was resulted from both thrombopenia and venous congestion due to compression of the mediastinal tumor.
Therapy and clinical course: Cotton tamponade to epistaxis, heart tonics, blood transfusion, steroid hormones, 6 MP, and cyclophosphamide (Endoxan) were given with beneficial effects, but still leaving dyspnea and mediastinal tumor. Then, X-ray therapy in small dosis in total of 1, 375 r was tried for a period of 2 weeks with dramatic effects (Fig. 2 and 3). After several remissions by the administration of 6 MP the patient died of pneumonia 85 days after onset. Unfortunately agreement of autopsy was not obtained.
From the view-points of the site and bilateral development, the mediastinal tumor was counted as thymoma. If may be true, this case should be classified into either myeloblastoma (Moeschlin et al. and Heilmeyer) or thymic tumor-forming leukemia (Akasaki et al.). Akasaki et al. described 11 autopsied cases of leukemia accompanied by mediastinal tumor and contrary to the commonly available opinion, they found that 10 of them were myeloblastic and only one was lymphocytic.
Lastly, it should be emphasized that epistaxis and dyspnea, including mediastinal tumor could be initial manifestations of leukemia, and careful X-ray therapy might be of emergency choice to critical dyspnea in such case.

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This myeloma case has been reported here because it is very interesting in findings of protein. Multiple myeloma is marked by malignant proliferation of plasma cells in the bone marrow. Usually the manifestations are rheumatic pain due to tumor formation in the marrow and abnormality of serum protein shows protein fractions with a electrophoretically characteristic sharp peak and abnormal protein is excreated in the urine.
A diagnosis of typical plasmocytoma is made on the basis of the myelogram, histological findings and electron-microscopic features of tumor cells in the bone marrow.
But we have had an experience with such a case where no abnormal proteins were observed in serum and urine. The patient, a 61 year-old-Japanese rice dealer, born in Tokyo, was admitted to Nihon University Hospital in Dec. 1962, because of cutting pain in the side and rachialgia. X-ray films of bones revealed multiple rounded and punched-out areas in the skull, globular tumor-formation and pathological fractures of ribs. The charactristic finding is “typical myeloma cells” in the marrow of sternum. These cells accounted for 75.2-78.6 per cent of all the cells, and were composed of plasmocytoma histologically.
Electron microscopically the endoplasmic reticrum and Golgi area were observed to be well-developed around the nucleus, and evidence suggesting extracellular excreation of proteins was also noted. Despite the fact that each fraction of the serum did not show abnormality in ultracentrifugation and immunoelectrophoresis. There was a slight increase in the amount of α-globulin in Tiselius and paper electrophoresis.
A minor anomaly type of multiple myeloma is usually a disease in which abnormal protein is excreated in the urine, but not serum. The case in question differs from the minor anomaly type in that it is not abnormal in serum and urine.
It is unknown (a) whether tumor cells produce normal proteins, (b) whether even if abnormal proteins are produced these are destroyed rapidly out of the cells or (c) whether clinical testing in use today cannot detect these abnormal proteins. In our opinion, these abnormal proteins might be present, but could not be identified by means of any currently available clinical test.

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It has been recognized that the plasma from an animal placed in low oxygen pressure, after hemorrhage, or made anemic by injection of phenylhydrazine had a hematopoietic action and the presence of erythropoietin has become certain. Elucidation of its principle was attempted by many workers and acidified and boiled plasma was chiefly used as its source material, utilizing its thermostable and acid-resistant characteristics.
Electrophoretic examination suggests that the substance might be a glycoprotein belonging to α₂-globulin but opinions differ as to its chemical principle, and a purified substance has not been obtained as yet.
Experiments were carried out in our laboratory based on the consideration that a series of research on the elucidation of erythropoietic factor would be theoretically possible when an essentially known substance is used.
It was reported by us that ceruloplasmin first isolated by Holmberg, the copper bound glycoprotein, has a hematopoietic action in its reduced form.
Porcine ceruloplasmin was used as crystalline form. As the experimental result obtained with the crystalline ceruloplasmin and apoceruloplasmin, presence of erythropoietic activity in apoceruloplasmin was proved by the measurement of the rate of Fe⁵⁹ incorporation into peripheral erythrocytes of the rats. Ceruloplasmin which has bivalent copper bound with apoceruloplasmin and presents in normal animals has no erythropoietic activity. Apoceruloplasmin, obtained by removal of copper from ceruloplasmin, has an erythropoietic action, but is naturally labile.
Consequently, apoceruloplasmin prepared in vitro often has different erythropoietic activity in each product, and sometimes has no activity.
So a method was devised to obtain erythropoietic substance with constant and stable activity, and in a constant yield from ceruloplasmin molecule.
Ceruloplasmin solution, diluted with distilled water to contain 0.05 mg/ml, was adjusted to pH 4.5 with N/6 hydrochloric acid and centrifuged at 3000 r.p.m. for 10 minutes. The precipitate thereby formed was dissolved in 0.1 M Na₂ HPO₄ to form a yellowish solution.
This acid precipitated substance has an erythropoietic activity and was not changed in activity at all after boiling at 100°C for 10 minutes.
Examination of the yield was 3.0-5.0 per cent of the amount of original ceruloplasmin.
This substance might be a subunit of ceruloplasmin molecule. Molecular weight of this substance was confirmed to be less than 80000.
Since the erythropoietic substance is separated from ceruloplasmin molecule, it may be possible that erythropoietin is formed in vivo from ceruloplasmin belonging to α₂-globulin.
Further detailed chemical analysis are now being carried out to obtain purified substance.

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1) Fe⁵⁹ uptake of the red blood cells decreased remarkably in rats starved from 3 to 5 days.
2) A factor, which lowered the Fe⁵⁹ uptake, was demonstrated in the serum of rats starved from 3 to 7 days.
3) Although the decrease of Fe⁵⁹ uptake in the starved rats was thought to be dependent upon the decrease of the erythropoietin level, the effect of the inhibitor should be taken into consideration.
It is suggested that the inhibitor does not act directly on the erythropoiesis, but blocks the activity of the erythropoietin at some point.

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1) Transferrin was determined immunochemically with the anti-human transferrin rabbit serum, which precipitated specifically transferrin as demonstrated by Ouchterlony's double diffusion method and immunoelectrophoresis. A linear relationship was found to exist between the immunochemically determined transferrin level and the chemically estimated TIBC in various diseases. In 87 cases of clinical cases, the ratio of TIBC to immunochemically determined transferrin level was 1.29±0.028 μg of iron per milligram of transferrin. Hypertransferrinemia was observed in iron deficiency anemia (essential hypochromic anemia, agastric iron deficiency anemia, peptic ulcer with occult bleeding, hook worm anemia), Banti's syndrome with hyposideremia and acute hepatitis. Hypotransferrinemia was found in liver cirrhosis, nephrotic syndrome, gastric cancer, rheumatoid arthritis and chronic granulocytic leukemia. In 17 cases of liver diseases, the serum transferrin level correlated most significantly with serum albumin fraction. Those with positive turbidity tests (TTT, ZST, Takata) showed significantly low serum transferrin level as compared with those with negative reaction. Based on these findings, the hepatic origin of transferrin was presumed. Transferrin excreted in the urine of 6 cases of chronic nephritis was determined immunochemically and was proved to comprise 4.1 (2.2 to 6.9) percent of the total urine protein.
2) The turnover rate of human transferrin was investigated by following the disappearance of intravenously administered iodinelabelled transferrin in normal subjects and patients suffered from various diseases. In 4 normal subjects the following mean and range values were obtained.
Half time 11.0 days (10.5∼12.1)
Transferrin turnover rate 6.3 percent/day (5.7∼6.6)
19.6 mg/day/kg (15.9∼23.3)
In the cases of essential hypochromic anemia was observed a longer half-time and a greater exchangeable pool than those of normal controls, but the cases of iron deficiency anemia with slight gastrointestinal bleeding showed a shorter half-time than that of essential hypochromic anemia. In the cases of liver cirrhosis, the serum transferrin and exchangeable pool were decreased. but the half-time was normal. In the cases of chronic nephritis (nephrotic form), the half-time was short and the exchangeable transferrin pool was small as compared with those of the normals.
3) Rat transferrin was isolated using rivanol and column chromatography on ion exchange cellulose. Anti-rat transferrin rabbit sera were prepared and they reacted specifically with the rat transferrin as shown by immunoelectrophoresis. The transferrin formation was demonstrated by determining the incorporation of glycine-2-C¹⁴ into the transferrin fraction of supernatant of liver slices in vitro. The quantity of the glycine incorporation was 1.7±1.17 (10^-3 μM/mg-protein/hr) in normal rat liver. The incorporation of glycine-2-C¹⁴ into the transferrin of spleen supernatant was negligibly small. In iron deficient rats with hypertransferrinemia, was observed a higher incorporation into the transferrin of liver supernatant, while in cirrhotic liver with hypotransferrinemia the incorporation was lower than that of normal controls. Based on these results, it would be reasonable to presume the increase of transferrin formation in iron deficient and the decrease of that in cirrhotic liver.

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At present abnormality of iron metabolism in iron deficiency anemia is considered by most of hematologists to be merely due to shortage of iron in the body. However, from results obtained in a series of following clinical and experimental studies, we presume that iron incorporation into erythrocytes and distribution of iron are still under control of a certain mechanism also in the anemia of this kind.
1) Elevation of hemoglobin level following administration of iron, either orally or parenterally, is variable from case to case.
2) Elevation rate of hemoglobin by iron administration largely depends on the initial level of hemoglobin.
3) Elevation rate of hemoglobin is influenced by administration of protein anabolic hormone or adrenocorticosteroid hormone.
4) In some cases, changes of hemoglobin level following menstrual hemorrhage are too large to be explained by only loss of iron during hemorrhage.
5) Increased iron incorporation into erythrocytes and rapid disappearance of iron from plasma are observed by administration of protein anabolic hormone in the phlebotomized rabbits. Iron distribution in the body is also altered by this treatment.

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Using the data concerning 102 cases of aplastic anemia admitted to this clinic from 1949 to 1961, the relationship between the initial findings of routine hematological examinations and the mortality rate was studied. From these results, a trial to decide the grade of severity in aplastic anemia was made. The results of this study are as follows;
1) The severity points in each case were calculated from the initial laboratory findings (nuclear cell counts of the bone marrow, RBC, reticulocyte, WBC, the percent of lymphocyte, thrombocyte, bleeding time and fever).
Following the number of these points, the severity of aplastic anemia was devided to 4 groups.
Group I mild cases, which have 1 or 2 points, Group II the intermediate cases (3 or 4 points), Group III severe cases (5 or 6 points) and Group IV very severe cases (7∼10 points).
2) This severity represented a remarkable relationship to the mortality rate. The mortality rate of I, II, III, and IV groups were 14.3%, 27.8%, 57.7%, 86.1%, respectively.
3) This severity showed a lineal relationship to quantity of blood transfused and the dosage of steroids used in treatment.
4) None of the cases in Group IV (very severe cases) treated by blood transfusion alone or combined use with folic acid survived, but cases of the same group treated by combined use of adrenocortical steroids showed the survived rate of 31%.
5) The degree of improvement during treatment may be shown objectively by the percent of severity points after treatment compared with the initial number of severity points at the beginning.
6) This grading of severity is not only useful for estimating the prognosis of aplastic anemia, but also important for comparison and appraisal of the effectiveness of some therapeutic agents.

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This probably is the first definite case in Japan, although another cases were presented by KAWAKITA, and YAMAGATA et al.
A 67-year-old housewife was referred to the Hospital in July, 1959, because of glossitis for 2.5 years.
No menses since 30 years of age when she was irradiated for control of abnormal uterine bleeding. At the age of 53 developed an intestinal obstruction, surgically treated. Five years later reoperated because of volvulus.
In January, 1957, seven years after the second operation, she found her tongue red and sore. Shots of riboflavin, however, had little effect. A gastrointestinal series at another hospital in May was not remarkable.
On admission, this small, thin woman complained of nausea, vomiting, anorexia and dizziness. There were glossitis with erosions and ulcers, venous hum, a grade 1 apical systolic murmur, meteorism and hyperactive peristalsis in the lower abdomen, numbness in the right leg, and sluggish tendon reflexes. No jaundice, lymphadenopathy, splenomegaly, edema, or steatorrhea. Intestinal X-ray examination revealed no obvious change.
A considerable hyperchromic anemia, leukopenia, and erythroblastosis (Table 1 and 3). Bleeding time was 6 min., platelet count normal, and a tourniquet test negative. Sternal marrow appeared rather hypocellular (Table 2, Fig. 5): 19 per cent of erythroblasts were megaloblastic (Fig. 1 and 2), 44 per cent intermediate, and the remaining normal. Also, hypersegmented neutrophils (Fig. 4) and giant immature forms (Fig. 3). Acid gastric juice and serum protein of 5.4 gm. per 100 ml.
On daily intramuscular vitamin B₁₂ the glossitis, neurologic findings and bone marrow abnormalities rapidly improved, but macrocytic anemia and hypoplastic marrow persisted (Table 2 and 3, Fig. 7). On Aug. 17, discharged on vitamin B₁₂.
On the second admission, 7 months later, physical examination revealed a remarkably pale, ill woman with a mild fever, widespread petechiae, and no glossitis. Considerable pancytopenia and panmyelophthisis (Table 2 and 3, Fig. 6) were present. On the sixth hospital day, sudden death after a transfusion of erythrocyte suspension. No autopsy.
FABER admittedly described an original case of pernicious anemia associated with intestinal obstruction that might be attributed to a process now called Crohn disease. Since then appeared a number of excellent reviews, showing that either intestinal diverticulosis or anastomosis as well as obstruction may cause megaloblastic or macrocytic anemias. The nature of the disorder has not been necessarily elucidated. The above-mentioned case obviously had a symptomatic megaloblastic anemia well responded to vitamin B₁₂, and also a fatal macrocytic aplastic anemia. The pathogenesis of such anemias, therefore, must be very complicated.

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In Japan megaloblastic anemia is rarely found. From 1903 to 1962, 449 cases of megaloblastic anemia were reported in Japan. Out of these cases there were 297 cases of Addison-Biermer's anemia, 99 cases of megaloblastic anemia in pregnancy and 20 cases of megaloblastic anemia following gastrectomy. The cases of megaloblastic anemia associated with gastric carcinoma were very rarely reported. There is only one family with two cases of Addison-Biermer's megaloblastic anemia in Japan found by the author.
Symptoms and signs, blood picture, bone marrow finding, bleeding time, clotting time, hemolytic index, erythrocyte life span, iron metabolism, circulationg blood volume, liver function, etc. were discussed.
Observation of gastric juice acidity revealed absence or decrease of free hydrochloric acid in many cases of Addison-Biermer's anemia. Namely, hypochlorhydria occurred in 60 cases, achlorhydria in 46 cases. On the other hand, free hydrochloric acid was normal in 13 cases and increased in one case.
Diagnostic criteria in megaloblastic anemia and morphology of megaloblasts including phase contrast microscopic finding and electron microscopic finding, etc. were described.
Finally, the treatment of megaloblastic anemia and interesting cases observed by the author were described.

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Following results were obtained from our clinical studies on anemia in patients with cancer of the gastro-intestinal (G-I) tract and of the lung:
(1) In patients with cancer of the G-I tract anemia developed from the earlier stage of the disease. In patients with severe anemia, erythrocytes were obviously hypochromic. Serum iron concentration was reduced significantly, especially in cases of severe anemia, although significant increase in UIBC was observed in the early stage of the disease. There was a significant correlation between the mean of daily blood loss through the G-I tract determined by the Cr⁵¹-method and Hb levels in peripheral blood. In these cases, the apparent intravascular survival time of Cr⁵¹-labeled. erythrocytes was the more markedly shortened, the greater the amount of blood loss into the G-I tract. Ferrokinetic studies revealed a marked shortening of PID and earlier utilization of Fe⁵⁹ by erythrocytes. Percentage red cell utilization of Fe⁵⁹ reached 80-100% in all cases. Absolute reticulocyte count was within or above normal range. Increase in both erythroblast and megakarocyte counts was the characteristic pattern of the bone marrow in patients with severe anemia.
(2) In most of the patients with pulmonary cancer without severe complications or overdoses of anti-cancer medication, anemia developed in the late stage of the disease. The apparent survival time of erythrocytes, which was within normal ranges in earlier stage, was significantly shortened in the late stage of the disease. Serum iron level was decreased or low normal in most of the patients, although the decrease was less marked than in cases with cancer of the G-I tract. In ferrokinetic studies, PID was normal or shortened while % RCU was normal. Absolute reticulocyte count was within normal in most of the cases.
(3) From the results above described, it is concluded that the anemia developed in patients with cancer of the G-I tract results mainly from blood loss through the G-I tract, while anemia in patients with pulmonary cancer ensues from the shortening of erythrocyte survival time observed in late stages of the disease. In most of the anemic patients with cancer, however, the increased rate of erythrocyte elimination may be compensated by an enhanced production, if the erythropoiesis were accelerated to the full physiological capacity of the bone marrow. Hence, a possibility of the relative insufficiency of the erythropoiesis should be taken into consideration. Further investigation is required to elucidate the cause of the relative bone marrow insufficiency.

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The science of biochemical genetics in human being began with the early clinical observations of Garrod on the so-called inborn errors of metabolism. The concept of the one gene-one enzyme has proved to have increasing applicability in clinical medicine.
Recent surveys show the presence of some hemoglobinopathies in Japan. These surveys may provide clues not only to the origin & the distribution of human races, but also to the biochemical approach for the heterogeneity of hemoglobin molecules.
After brief review on what seem to us the understanding recent development on hemoglobin biochemistry, with respect to genetic knowledges, we discuss the various cytochemical, immunological, & physicochemical behaviors of the fetal hemoglobin.
Our studies including polarographic observation & amino acid analysis of normal & such abnormal hemoglobin as we found in thalassemia minor & hereditary persistence of high fetal hemoglobin with the aids of polarography & automatic amino acid analyser, lead us into certain preliminary attempts to explore the heterogeneity of protein molecules utilizing the differences between hemoglobin A & F as a guide.
Cytochemical studies of red blood cell with the aid of Betke's smear method & fluorescent antibody technique reveal proportional number of positive cell to an amount of alkali resistant hemoglobin demonstrated by Singer's method. Our studies on various anemia suggests that an elevated fetal hemoglobin may stem either from (1) a mixture of red cells with different amounts of fetal hemoglobin or (2) a red cell population in which every cell has the same amount of fetal hemoglobin.
Such precise studies with fluorescent antibody technique & in vitro synthesis incubated with nucleoprotein containing different genetic information, which is now under our study, has a direct bearing on the problem of cellular differentiation as well as the concept of operator & regulator gene described by Jacob & Monod, & the resulting loss of potentialities for the specialized cell. These facts allow us to look into the mechanism of the specificity of hemoglobin synthesis & also to find the means of connecting the observed defects.
Conclusively, mutational events in human genetics are considered in terms of regulatory mechanisms involving control genes & structural genes in the genetic materials and specific models, developed in bacterial genetics, are applied to the hemoglobin synthesis in man.

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Followings are the results of the studies on flve cases of thrombasthenia (Glanzmann). On each patient splenomegaly was recognized.
1. There was no evidence of any characteristic morphological changes on megakaryocytes examined by stained bone marrow smears. However, conglomerates of the platelets around the megakaryocytes seemed to be scanty.
2. No abnormality was obtained in blood clotting factors, so far as our studies concerned. Thrombelastogram revealed that the r-value and k-value were normal, whereas ma-value was abnormally small.
3. Ultra structure of the platelet was investigated under the electron microscope; granulomere αrevealed unique morphological abnormality and its electron density was greately increased. Another impressive facts were that the endoplasmic reticulum were markedly swollen, and cytoplasmic microgranules were increased in both numbers and size accompanying with high electron density.
4. The platelet fragility was determined according to the method of the author and col., which disclosed within normal.
5. During the clotting process, most of the Patients' platelets did not adhere to the fibrin filaments.
Usually, the normal platelets clumped together and formed conglomerates as soon as clotting had started. Patient's platelets, however, did not formed such conglomerates.
6. ATP level in the platelets showed an uniform diminution. And, clot retraction was taken place by the addition of ATP to the patients' platelets. This ability, clot to retract, was enhanced by the further addition of Mg⁺⁺ to the platelet-ATP mixture.

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In this paper the fibrinogen conversion test induced by G. Y. Shinowara are used to determine the hypercoagulability of the blood from the patients with thrombosis. The authors could demonstrate the enhancement of the fibrinogen consumption by this test in some cases among the patients, especially in the patients who have been suffered from the progressive type of thrombosis before and after the performance of the test, although the data did not show any definite correlationship between the course after thrombus formation and the results of the test. According to this study showing the significant value of this fibrinogen conversion test, the enhancement of fibrinogen consumption in the cases with thrombotic disorders would be able to diagnostically suggest the further formation of thrombosis, and to indicate the simultaneous administration of anticoagulant drug in addition to the thrombolytic agents from the point of therapeutic purposes.

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Hemophilia or hemophilia-like hemorrhagic disorders are exceedingly rare in the female and acquired diseases of this type are rare in either sex. For example, Sise et al.¹⁾ in 1962 collected only thirty-nine cases of hemorrhagic disorders associated with a circulating anticoagulant. Only nineteen of this group were females of which four were over the age of 60. A still smaller group of cases presented an association of this type of hemorrhagic defect with abscess formation, necrosis or infection associated with tissue destruction.^2∼7) An extensive review of circulating anticoagulants in the various categories was given by Margolius et al.⁸⁾ in 1961.

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Secondary disease in rats receiving bone marrow transplantation from normal rabbits was slighter than in rats receiving bone marrow transplantation from rabbits sensitized with egg-albumin. Direct coombs test using anti-rabbit globulin serum was positive in rats receiving transplantation from above sensitized rabbits, while negative in rats receiving transplantation from normal rabbits. Generally speaking, a large amount of antigen suppress the antibody production. Therefore, the large amount of erythrocyte antigen may suppress the formation of anti erythrocyte antibody of transplanted rabbits immune competent cells, resulting in negative coombs test. However, transplanted immune competent cells of rabbits sensitized with egg-albumin were able to produce anti-erythrocyte antibody in spite of presence of a large amount of antigen. These results suggest that antigenic stimulus may cause some changes in antibody formation mechanism of immune competent cells to produce antibodies against a large amount of other antigens. Some changes in antibody formation mechanism in immune competent cells may be present in auto-immunization mechanism, because auto-antibodies are produced against a large amount of autoantigen. Possibility of changes in antibody formation mechanism due to prolonged sensitization and malignant neoplasm of lymphoid tissue was suggested.
Injection of I¹³¹ labeled anti-rat liver antibodies into normal rats resulted in specific high in vivo localization in liver. The absorption of anti-liver antibodies with liver homogenates sediments resulted in abolishment of localizing antibody, leaving precipitin against liver homogenates supernatant unaffected. Activity of localizing antibody was not affected by absorption with supernatant, while precipitin titer decreased markedly. When anti-liver antibodies were injected intravenously into normal rats, localizing antibody disappeared from circulating blood within 20 minutes, leaving precipitin against supernatant. These results suggest that anti-liver antibodies contain various antibodies produced against various antigen in liver homogenates. The antibody which localizes in liver and exerts cytotoxic effect is the antibody produced against liver homogenates sediments.
Therefore, we must be carefull to ascribe pathogenic roles to antoantibodies, which were demonstrated in patient's serum using tissue homogenate supernatant as antigen. These autoantibodies may suggest presence of autoimmunization mechanism in patients. However, they are not necessary etiologic factors of the disease.

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The relation of lymphocytes to antibody formation has been the light of subject of considerable study in the field of immunology. However, until the recent years, less evidences were shown for the conspicious role of lymphocyte with this activity. In 1950, Fukase demonstrated that the saline extract of lymph nodes contains a factor which distinctly accelerates the antibody formation when it is injected to a recipient with the antigen. This finding was supposed to suggest that lymphocytes may carry a promoting action for antibody formation. The present report deals with the further observations which successfully and clearly demonstrated important and creditable roles of lymphocytes in antibody formation. The results of our studies are summarized as follows.
1. When recipient rabbits were intravenously injected with typhoid bacilli (antigen) and destroyed lymphocytes obtained from the thoracic duct lymph, which consisted of almost entirely lymphocytes, of donor rabbits 3 to 4 days after the injection of antigen into the radical mesenteric lymph nodes, the agglutinin formation was rapidly and strongly promoted than that of rabbits received an antigen only. A less acceleration of antibody formation was observed when non-immunized and destroyed lymphocytes were injected into rabbits with the antigen.
2. When the microsome and supernatant fractions, which were prepared by differential centrifugation of immunized homogenized lymphocytes in 0.25M sucrose medium, were intravenously injected into recipient rabbits with antigen, the antibody formation was markedly promoted similarly to that of rabbit injected with the whole lymphocytes and antigen.
3. When a mixture of ribonucleic acid (RNA) and supernatant fraction of lymph node cells of sensitized rabbits was intravenously injected into recipients together with antigen, a rapid and marked rise in agglutinin titer was demonstrated. From these points of view, it is concluded that immunized lymphocytic RNA plays a main role in a promotion of antibody formation.
4. When recipient rabbits received intravenous injection of dysentery bacilli and destroyed lymphocytes which had been immunized with typhoid bacilli, the agglutinin formation against dysentery bacilli was not accelerated, while the destroyed lymphocytes immunized with dysentery bacilli showed a promoting action of antibody formation against dysentery bacilli, but not against typhoid bacilli. These observations indicate that lymphocytes immunized with A-antigen promote specifically the antibody formation to A-antigen, but not to the others. Furthermore, additional studies demonstrated that lymphocytes immunized with A and B antigens carry an ability to promote the antibody formation to both antigens.
5. The antibody formation promoting activity of lymphocytes was not observed in the recipient animals which are immunologically immature or following X-ray irradiation.
6. The sensitized lymphocytes were capable of accelerate not only the agglutinin but the precipitin formation as well as the tuberculin hypersensitivity.
7. On the basis of those results, a conclusion may be drawn that lymphocytes behave as the messenger of information of antibody formation.

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To examine the concept of the so called Banti's syndrome, 25 cases of longstanding splenomegaly of unknown etiocogy with some degree of disturbance of hematopoiesis were collected and their clinical findings, hematological functions, hemodynamics in portal system and histological findings in liver and spleen were investigated. From this investigation, it was possible to divide these cases into three different categories. Group A consists of the findings of infectious spleen, and group C of the findings of liver cirrhosis associated with splenomegaly, Group B demonstrated hypochromic iron deficiency anemia, leukopenia, thrombocytopenia, and portal hypertension, and thought to be the group which should be called as Banti's syndrome in the strict sense of the meaning. This group demonstrated further, typical histological findings of so called Banti's spleen and liver. The portal hypertension was thought to be the secondary phenomenon due to the pathological changes occuring in the liver, such as the fibrosis starting in portal tract. The unknown etiological factor, a some sort of noxious agent which has certain affinity to both liver and spleen was thought to be working. No signs of liver cirrhosis or extrahepatic portal obstruction were found in the group.

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Accurate appraisal of the entire lymph nodes in patients with various malignant blood disorders is of considerable importance for the diagnosis, treatment, follow-up and prognosis. It has been recently recognized that the technique of lymphography is very useful for these purposes. It is even more important in the study of areas not readily palpable, especially the retroperitoneal space, the mediastinum and even the apex of the axilla. According to the method of Kinmonth, lymph vessels were exposed after injecting patent blue subcutaneously in the dorsal region of the feet and hands and visualization of the lymphatic system was accomplished by injecting contrast materials (Lipiodol Ultrafluide or Ethiodol) directly into the exposed lymph vessels with the injector consisting of a manually-operated screw arrangement for advancing the plunger of the syringe containing the opaque medium.
Patients with leukemia and allied disorders studied by this technique included 1) acute lymphocytic leukemia, 2) chronic lymphocytic leukemia, 3) acute myelogenous leukemia, 4) chronic myelogenous leukemia, 5) reticulosarcoma, 6) lymphosarcoma, 7) primary macroglobulinemia (Waldenström), 8) giant follicle lymphoma, and 9) eosinophilic granuloma. Normal lymph nodes appear as round, oval or spindleshaped masses with a variable size, averaging approximately 1.5 to 2 cm. in maximum dimension. Each has a distinct margin. The internal architecture has a homogeneous reticular pattern. In leukemia and allied disorders, the pattern of the lymph nodes is characteristic. There is a general increase in the size and in the number of the lymph nodes, however, the borders remain intact. The interior pattern of the lymph nodes is coarsely granular or linear in acute leukemia and lymphosarcoma, mottled or foamy with flocculent areas of increased density in chronic lymphocytic leukemia, and finely reticular or honey-comb in reticulosarcoma. The pattern of the lymph nodes in macroglobulinemia and giant follicle lymphoma resembles that in acute leukemia, and that in eosinophilic granuloma is similar to the normal pattern. Since these lymph nodes can be visualized from several weeks to months without further injection, it is possible to observe the gradual regression of the enlarged lymph nodes following chemo- and radiotherapy. In this paper comparative studies of the lymphograms in malignant blood disorders, metastatic carcinomas, and inflammatory diseases are presented.
On the basis of these findings, the authors conclude that the clinical value of lymphography in haematological practice is great and emphasize the desirability of its popularization as a new laboratory technique.

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