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The in vitro response of lymphocytes to phytohemagglutinin (PHA) was correlated with various clinical features in seventy-eight patients with Hodgkin's disease. PHA response was normal among patients in remission, except in a few instances in which depression could be attributed to antecedent radiation or chemotherapy. PHA response varied greatly among patients with active Hodgkin's disease and appeared to be affected by a variety of factors related to the disease and to treatment. Radiation therapy induces a profound but temporary depression of lymphocyte response to PHA. Chemotherapy for Hodgkin's disease also depresses lymphocyte responsiveness to this agent, but less markedly and less consistently than radiation. We conclude that measurement of lymphocyte response to PHA does not provide a dependable assessment of a patient's immunologic competence or clinical status and that further investigation is needed to define the clinical significance of this laboratory test of lymphocyte behavior.

FOR many years there has been disagreement over the incidence of carcinoma of the thyroid gland. Some authorities have claimed that it is a relatively common disease, and others have maintained tha...

The uptake of oleate by the isolated perfused rat liver was studied over the range of plasma free fatty acid (FFA) concentration from 100 to 1,800 µEq/liter. Hepatic removal of FFA could be described as a linear function of the FFA concentration in blood entering the liver. When appropriate correction was made for the difference in metabolic rates of the two species, it was found that the isolated rat liver removed FFA from its perfusing blood at rates quite comparable to those reported for the dog liver in vivo. An effect of glucagon on FFA uptake rates could not be demonstrated, either with fasted or with glycogen-containing livers. This experimental system, which offers the advantages of relatively easy control of many variables and of exclusion of the effects of other organs, appears well suited for studies of fatty acid metabolism in the liver.

Three cases of myeloid leukemia (acute myeloblastic leukemia, chronic myelocytic leukemia, erythroleukemia) were observed among a population of patients with Hodgkin's disease. Chromosome ...

Glycogen metabolism was studied in isolated rat liver, using the perfusion apparatus developed by Miller ( J. Exper. Med. 94: 431, 1951). It proved possible to maintain stable glycogen levels for as long as 3 hours in this system, at glucose concentrations of 200–300 mg% in the perfusing blood. Glycogen synthesis was observed in isolated livers obtained from fasted animals, at glucose concentrations entirely within the physiological range. At high glucose concentrations, glycogen levels reached 2% or more. Glycogen synthesis was observed both with and without insulin, but it took place at lower glucose concentrations when insulin was added. Infusion of epinephrine induced glycogenolysis in the isolated liver. Norepinephrine was less active as a glycogenolytic agent.

CONSIDERABLE information has accumulated in the medical literature about the effects of desacetylmethylcolchicine,§ an alkaloid with antimitotic properties closely related to colchicine, since its recent introduction as a therapeutic agent in gout and in some neoplastic diseases, particularly chronic myelocytic leukemia. Published reports indicate that this drug has little toxic effect upon the liver when used within the therapeutic dose range of 3 to 6 mg. daily. Some authors suggest that the possibility of hepatotoxicity exists, although the nature or the degree of the hepatic alterations has not been determined in the clinical experience. Storti and Gallinelli1 observed a case . . .

Increases in hepatic phosphorylase activity and glucose release were often observed when 5 ng of glucagon was added to 100–120 ml of blood perfusing an isolated liver, and regularly followed additions of 10 ng. Under the conditions of these experiments, maximal activation of phosphorylase was seen after glucagon additions of 80–100 ng and maximal hepatic glucose output, after additions of 250–500 ng. These effects of glucagon can be used for bioassay of the hormone. Because of the variability of responses recorded in different liver perfusions, such bioassay is semiquantitative rather than precise. However, if unknowns can be assayed in several liver perfusions, reasonably accurate mean values are obtained. The isolated perfused liver provides a considerably more sensitive and specific assay for glucagon than other methods based on biologic activity of the hormone, and discriminates between true glucagon and immunologic cross-reactants. If large samples are available, its sensitivity can approach that of ...

BCG is a potent immunologic stimulant which can increase cellular immune responses generally, as well as induce sensitivity to tuberculin. A single BCG vaccination induced significant increases in delayed hypersensitivity responses of patients whose neoplastic disease was under good control. Repeated vaccinations exerted cumulative effects, and very substantial increases in delayed skin test responses to a battery of antigens were seen in some groups of patients. The major determinant of responsiveness to these effects of BCG was the status of the neoplastic disease. Patients with uncontrolled, actively progressing disease showed little immunologic response to BCG vaccination.

Desacetylmethylcolchicine decreased the leukocyte count and produced reduction or disappearance of immature cells in the peripheral blood in all of 14 patients with chronic myelocytic leukemia. These effects were usually accompanied by regression of splenomegaly and hepatomegaly, rise in hemoglobin concentration, and subjective improvement. A beneficial effect was also observed in some cases of blastic crisis. This drug appeared to have greater selectivity of action against cells of the granulocytic series than other antileukemic agents. Continuous adminstration proved necessary to maintain remission. Regulation of dosage was difficult; hematologic relapse occurred with suboptimal doses and toxic manifestations occurred with doses above the optimum. The drug's principal advantages are: prompt therapeutic action, possible effectiveness against myeloblastic proliferation, and rapid reversibility of its toxic effects.

THE mechanism whereby bacterial infections induce fever has been elucidated in some detail1,2. Bacteria and bacterial pyrogens (exogenous pyrogen) interact with polymorphonuclear granulocytes of the host, resulting in release into the circulation of a soluble product of the granulocyte (endogenous pyrogen) which is the proximate cause of the fever through its action on the temperature control centre of the host. Exogenous pyrogen arid endogenous pyrogen may be distinguished in several ways, but the most striking difference between their actions is that tolerance to the first develops rapidly, whereas endogenous pyrogen continues to cause fever after a long sequence of daily injections.

The possibility of dissolving a recent thrombus by the intravenous administration of a fibrinolytic enzyme was studied in a series of patients. Fibrinolysin (plasmin) was prepared in several ways from human and bovine plasma, and preparations were obtained from other laboratories also. Altogether 114 infusions of fibrinolysin were given to 37 volunteer patients, most of whom had incurable cancer. Thirteen episodes of acute thrombophlebitis, occurring in 10 patients of this series, were treated. In five of the eight cases in which the age of the thrombus was three days or less, complete resolution was obtained. When improvement did occur, the pattern of response was fairly uniform; pain was relieved within 24 hours, color improved and tenderness disappeared shortly thereafter, and edema disappeared within a few days. The results, which were sometimes striking, are illustrated in 14 case histories. Fibrinolysin was ineffective when given a week or more after the first manifestations of thrombosis, and it did not prevent the formation of fresh thrombi. The mechanism of its action upon blood clots in vitro as well as the clinical experiences here reported argue in favor of simultaneous administration of anticoagulants with fibrinolysin in the management of acute thromboses.

W.B., a 38-year-old Negro, had previously been treated with sulfonamide ointment for dermatitis herpetiformis. On June 5, 1966, oral sulfapyridine, 2 gm daily, was started for a recurrence. Two wee...

Intravenous injection of 1–2 μg/kg of glucagon produced greater and more persistent effects on liver glycogen and blood glucose of dogs than 10–50 μg/kg of epinephrine. When administration was by portal vein infusion, glucagon appeared to be more than 100 times as potent a glycogenolytic agent as epinephrine. Epinephrine produced greater effects via the femoral vein than when infused into the portal vein; It is concluded that in the dog, as well as in the rat, only glucagon can serve as a physiologic hepatic glycogenolytic agent, and that the effect of moderate doses of epinephrine on the liver is an indirect one, possibly mediated through stimulation of glucagon secretion. (Endocrinology 78: 47, 1966)

Little attention has been focused on the liver as a source of embolic fat. Despite this, clinical observations are available suggesting a relationship between fatty livers and the frequency and/or degree of fat embolization. By combining whole organ perfusion techniques and dietary production of fatty livers in experimental animals, a tool for evaluating the liver and its role in fat embolization has been developed. Fatty livers were produced in adult rats within 12 days by employing a high fat choline-free diet. One group of animals so prepared served as nonperfused tissue controls. Livers from normal and special dietary animals were removed and perfused for periods up to 4 hr. All tissues were frozen and then sectioned after 24-hr fixation in 10% formalin and stained with flaming red and hematoxylin. Nonperfused livers from animals on a choline-free diet revealed intense intracellular lipid concentration, but no fat emboli. Normal livers perfused for 3—4 hr were free of significant accumulation of embolic fat. In contrast, severe embolization was encountered in the perfused fatty livers. Note: With the Technical Assistance of Kornel Gerszi and Mary S. Northington Submitted on May 10, 1961

Scanning of the thyroid and of extrathyroidal tissues after the administration of a tracer dose of radioactive iodine has proved to be a very useful diagnostic tool in the study of thyroid disease. This technique permits the mapping of functioning and nonfunctioning areas of the thyroid and makes possible the localization of other areas of iodine concentration which may represent ectopic thyroid tissue or metastatic lesions of thyroid cancer. Several authors have reported that scintiscans of the thyroid are useful in the differentiation of benign thyroid nodules from others which may be malignant. 1-5 Since thyroid carcinoma rarely, if ever, concentrates iodine as well as normal tissue does, malignant thyroid nodules usually appear as hypofunctioning or nonfunctioning areas in the scintiscan. This has led to the proposal that the scintiscan be used to determine which goiters may be treated medically and which should be extirpated surgically. It has been stated that

Antagonism was demonstrated between the effects of insulin and glucagon, added simultaneously to the perfusing blood, on phosphorylase activity, glucose output and urea production of the isolated rat liver. However, the degree of antagonism varied greatly, according to the action under study, and there appeared to be a clear-cut hierarchy in the effects of each hormone. For glucagon, this was (stimulation of): (1) phosphorylase activity, (2) glycogenolysis and glucose release, (3) urea production. For insulin, it was (inhibition of): (1) urea production, (2) glycogenolysis, (3) phosphorylase activation. Thus, high concentrations of insulin completely failed to inhibit the phosphorylase activation induced by 1.4 mμg./ml. of glucagon, while modest concentrations of insulin totally suppressed the stimulation of urea production induced by sustained glucagon concentrations at least ten times greater, and well above the biologic range. Our findings argue against a single common primary site of action of these two hormones.

Excerpt Discovery of the Philadelphia chromosome (Ph1) in cases of chronic myelocytic leukemia (1) provided the first demonstration of a specific chromosomal abnormality in a human neoplasm. Howeve...

Measurement of delayed skin-test responses is a basic clinical procedure, originally used for identification of infection with microbial agents. More recently, skin testing with a battery of antige...

Hsia and Kot1 have reported that children with liver glycogen disease (von Gierke's disease) and their parents, presumably heterozygous for the disease trait, both have high levels of glucose-6-phosphate and fructose-6-phosphate in red blood cells. If correct, this observation would have very important practical as well as theoretical implications. It would greatly simplify the diagnosis and study of this disease and would open the possibility of its control through a eugenic approach. However, Hsia and Kot presented no evidence that their analytical methods were appropriate or that the materials they measured were in fact glucose-6-phosphate and fructose-6-phosphate. Furthermore, the values these authors cited for their normal control population (glucose-6-phosphate, 50–370 mgm. per 100 gm. red blood cells; fructose-6-phosphate, 120–570 mgm. per 100 gm. red blood cells) are much higher than those reported by other investigators2,3 or expected from theoretical considerations. Accordingly, their findings seemed questionable. We have re-examined this problem with respect to glucose-6-phosphate, using a specific enzymic analytical method. Our results are in sharp disagreement with those of Hsia and Kot.

Pregnancy is not a common complication in cancer. When it does occur, it often does not affect greatly the treatment of the malignancy, although it may change the prognosis. Occasionally, however, pregnant women with disseminated malignant disease are seen as candidates for palliative therapy with irradiation or chemotherapeutic agents. In such cases, the presence of the pregnancy may be a major factor in determining the therapy to be given. Although various types of cancer may occur in patients of childbearing age, the subject of cancer chemotherapy during pregnancy has been important principally in the leukemias and lymphomas, so far, since it is in these diseases that chemotherapeutic agents have been most widely used. As the use of chemotherapy is extending to other types of malignancy, however, this problem will become a more general one. A major factor in reaching decisions regarding therapy in pregnant women is the possibility of producing

Administration of 75 μg of sodium liothyronine per day for 12 weeks resulted in a measurable decrease in the size of nontoxic goiters in about half of 46 patients. No nodules disappeared during these short courses of thyroid-suppressive therapy; in most cases, decrease in goiter size was relatively slow, and measurable changes were often not observed until after 8 weeks of therapy. Suppression of thyroidal iodine uptake or of endogenous hormone secretion was not necessary in order to obtain reductions in goiter size. This suggests the possibility that treatment of goiter with thyroid hormones could be reduced to a simple routine by using moderate doses for all patients and by omitting iodine uptake studies and determinations of protein-bound iodine.

Many congenital metabolic disorders can be diagnosed by a relatively simple blood or urine test. Furthermore, in some recessive hereditary diseases, asymptomatic heterozygous carriers can be identified by appropriate biochemical procedures. Recently, Hsia and Kot 1 reported that identification of patients with liver glycogen disease (von Gierke's disease) as well as heterozygous carriers of the presumed causative genetic trait, was possible by determination of phosphorylated hexoses in circulating erythrocytes. They claimed that children with this disease, and their parents, have elevated levels of glucose6-phosphate and fructose-6-phosphate in their red blood cells. These findings have since been cited in other publications. 2,3 If correct, this observation would have very important practical as well as theoretical implications. It would greatly simplify the diagnosis and study of this disease and would open up the possibility of its control through a eugenic approach. However, a disturbing feature of the report of Hsia and Kot

Liver glycogen disease (von Gierke's disease) is a rare and incompletely understood disorder of childhood, characterized by high concentration of glycogen in the liver and by inadequate release of glucose from this organ into the circulation. Major clinical manifestations include hepatomegaly; fasting hypoglycemia, acidosis, and ketosis; delayed growth and sexual development; and increased morbidity from infections. Some affected children have a bleeding diathesis, manifested principally by epistaxis, which may be sufficiently frequent and severe to cause hypochromic anemia. Hyperlipemia and accumulation of fat in the liver are very common, and the concentration of fat in the liver frequently exceeds that of glycogen. Histologic study of autopsy or biopsy specimens of liver reveals essentially normal architecture in almost all cases, but hepatic cells contain excessive amounts of glycogen and usually, fat. In some patients, glycogen accumulation appears to be limited to the liver; in others, tissues such as kidney, skeletal muscle

Excerpt Prognosis in Hodgkin's disease is notoriously difficult. Some patients die rapidly despite early and aggressive therapy, while others with various combinations of unfavorable prognostic sig...

Excerpt Patients with nontoxic nodular goiter were treated with T8, 50 µg/day, or T4, 200 µg/day, in a double-blind study. Their nodules were measured independently by two examiners at 4-week inter...

Excerpt Death from chronic myelocytic leukemia usually results from myeloblastic transformation. In 1965, efforts were initiated to prevent or delay such death by immunizing patients with cultured ...

Many papers have appeared during the past 10 years calling attention to the high incidence of cancer among nontoxic nodular goiters that are surgically treated. Different authors have presented their data in somewhat different ways. Most have included patients with known cancer, patients suspected of having cancer, and patients thought to have benign goiter in a single group and have given the percentage of cancer found in resected specimens for the entire group. Many have indicated that cancer was found much more commonly in thyroid glands with single nodules than in multinodular glands.1Others have pointed out, however, that it is very difficult to determine clinically just how many nodules there are in a particular gland and that preoperative classification on this basis is of relatively little value.2Some have stated that nodular goiters are more likely to be cancerous in men than in women.3All authorities

Excerpt Chromosomal studies were performed in 76 cases of chronic myelocytic leukemia (initial diagnosis) using a direct technique for examination of bone marrow cells, except for a few cases in wh...

The ability of skilled physicians to estimate cancer risk in nontoxic goiter was determined by reviewing 235 evaluations of patients referred as thyroid cancer suspects and comparing the diagnostic impressions with the subsequent clinical and histological findings. Of 202 patients classified as "benign" on clinical evaluation, 2% proved to have thyroid cancer. In contrast, 28% of those classified as "suspected of cancer" and 53% of those classified as "probably cancer" did indeed have malignant goiters. Furthermore, although only 63 patients with "benign" goiters were subjected to early thyroidectomy, these included all 4 with thyroid cancer so far identified in this group. These figures indicate that patients with goiter can be divided quite successfully into low and high cancer-risk groups and that preoperative selection is justified.

INTRODUCTION AND REVIEW OF THE LITERATURE The announcement by Minot and Murphy of the successful therapy of pernicious anemia by a liver diet served as a strong stimulus to the preparation and study of liver extracts. Although the primary interest of investigators has been in the effect of various liver extracts on the hemopoietic system and most of the studies have been confined to patients with pernicious anemia, there has been some consideration of the action of such extracts on other organ systems. With the introduction of injectable extracts in particular, animal experiments have been performed and various side actions of liver preparations have been studied. In the course of such studies of the systemic effects of orally and parenterally administered liver extracts, especially the latter, various observers have noted more or less striking effects on the carbohydrate equilibrium of the body. As might be expected with different men using