John Laszlo

Prognostic factors in metastatic and hormonally unresponsive carcinoma of the prostate.

Eighty‐eight patients with hormone‐resistant Stage IV prostate cancer were treated with a five‐drug chemotherapy program. Patient demographic data, prior therapy, symptoms, extent of disease, and laboratory studies were analyzed statistically to evaluate the association of these parameters with survival from the onset of chemotherapy. Factors associated with short survival included age >65, severe bone pain, poor performance status, presence of soft tissue metastases, anemia, elevation of serum LDH, SGOT, alkaline and acid phosphatases, and prolactin, and hypoalbuminemia. Race, stage at initial diagnosis, prior radiation therapy, prior orchiectomy, and elevation of CEA had no prognostic association. We suggest that clinical trials of new therapies of hormone‐resistant prostate cancer take into account the presence of these prognostic factors in the analysis of the results of therapeutic programs. Cancer 44:763‐775, 1979.

Nausea and Vomiting as Major Complications of Cancer Chemotherapy

SummarySignificant advances in the treatment of certain disseminated malignancies have been accompanied by an increased awareness of the consequences of inadequate antiemetic therapy. Nausea and vomiting are predisposing factors to patient non-compliance with treatment regimens and impose mental and physical suffering that diminishes the quality of life. The extent of medical complications associated with vomiting depends on its severity and duration and can include oesophageal tears, bone fractures, malnutrition and major metabolic derangements.The pharmacological management of chemotherapy-induced nausea and vomiting is influenced by the aetiology and mechanism as well as whether therapy is to take place in the hospital or outpatient setting. No single drug is successful in all cases. Side effects due to antiemetic drugs also limit their usefulness.Major treatment alternatives at present include the phenothiazines, antihistamines, benzquinamide derivatives, butyrophenones such as haloperidol, the dopamine receptor antagonist domperidone, and metoclopramide. Cannabinoids, particularly Δ-9-tetrahydrocannabinol and nabilone have stimulated considerable research interest. Studies of the role of high dose corticosteroids either alone or in combination with other antiemetics have also been undertaken.Newer chemotherapeutic regimens are more emetic than in the past. Inadequate management of nausea and vomiting is deleterious to the health and well-being of patients and any delay in providing an aggressive therapeutic approach aggravates the problem. This symposium is designed to provide some answers to this therapeutic problem.

Actinomycin D: Inhibition of Respiration and Glycolysis

Actinomycin D inhibited respiration and anaerobic glycolysis of human leukemic leukocytes and lowered the adenosine triphosphate content of the cells. Inhibitory effects on respiration and on RNA synthesis could not be dissociated from one another over a wide range of drug concentrations. Actinomycin D also impaired protein synthesis, probably by decreasing the availability of adenosine triphosphate and by inhibiting messenger RNA.

THE EFFECT OF 2-DEOXY-D-GLUCOSE INFUSIONS ON LIPID AND CARBOHYDRATE METABOLISM IN MAN

At the present time, the direction of change of the plasma free fatty acid (FFA) level is considered to serve as an index to the pattern of fat metabolism, representing an indicator of the balance between fat storage and fat mobilization. In the fasting, nonexercising individual, a rising plasma FFA level suggests net fat mobilization and a falling FFA level suggests net fat storage. If the status of carbohydrate metabolism does relate to fat metabolism, then plasma FFA levels may be expected to change in a number of experimental situations. Dole Was the first to (lemonstrate that glucose and insulin administration decreased fasting FFA levels (1) and Bierman, Dole and Roberts that patients with diabetes niellitus have high FFA levels (2). Experimental inteference with carbohydrate metabolism might also be expected to influence plasma FFA levels. The availability of 2-deoxy-D-glucose (2-DG) has made it possible to test this hypothesis. 2-DG is phosphorylated to 2-deoxyglucose-6-phosphate (2-DG-6-P), and it has been postulated that the 2-DG-6-P may compete for transport into the cell with glucose-6-phosphate (3). The purpose of this study was to observe the effect of 2-DG administration on FFA levels in normal human subjects and to study in addition the effect of glucose, insulin, fructose and lactate upon the pattern of response to 2-DG.

The occurrence and consequences of deoxyuridine in DNA.

Deoxyuridine can become resident in the DNA of prokaryotic and eukaryotic cells via two general mechanisms - deamination of cytosine to uracil, and nucleotide pool changes that lead to misincorporation of deoxyuridine in place of thymidine. In this paper we have examined the chemical basis of deamination reactions in DNA and discussed a possible mechanism for an increased rate of deamination by means of cross-strand protonation of cytosine by alkylated guanine. In addition, we have examined the genetic and drug-induced conditions that lead to dUMP misincorporation into DNA in place of thymidine and have presented experimental evidence indicating that the antifolate-induced lesion is a general drug-dose dependent lesion of human blood cells. Finally, the toxic and genetic impact of this lesion has been evaluated within the context of a review of the repair mechanisms elicited by dUMP in DNA.

Granulocytic leukemia and reticulum cell sarcoma

Two cases of granulocytic leukemia associated with reticulum cell sarcoma are reported. Reticulum cell sarcoma was diagnosed in one patient from lymph node biopsy during life and from histological evaluation of bone marrow sections postmortem; studies of peripheral blood and bone marrow aspirated 8 days before death, however, revealed changes of acute granulocytic leukemia. Reticulum cell sarcoma was diagnosed in the second patient 7 months before he developed the peripheral blood and bone marrow findings of chronic granulocytic leukemia. The relationship between these 2 entities is discussed and the authors suggest that they may represent the same basic disease process studied through 2 different morphologic methods.

DNA replication and degradation in mammalian tissue. I. Changes in DNA polymerase and nuclease during rat liver regeneration.

Abstract The incorporation of [3H]thymidine into rat liver DNA, DNA polymerase activity, and deoxyribonuclease activity have been compared at various times following partial hepatectomy of the rat. 1. 1. DNA polymerase activity increases when [3H]thymidine incorporation in vivo increased and remained elevated for at least 60 h following partial hepatectomy, despite waves of DNA synthesis. Fluctuations in nuclease activity were directly opposite to the peaks of [3H]thymidine incorporation at different times during regeneration. It is suggested that deoxyribonuclease plays an important role in the control of DNA synthesis. 2. 2. Rat liver polymerase had a preference for native DNA primer whereas deoxyribonuclease in the same preparation acted preferentially on denatured DNA. It is suggested that the apparent difference in polymerase primer preference is due to nuclease activity associated with the pH 5.0 protein fraction.

Mechanisms influencing conduction in a case of intermittent bundle branch block

Abstract A case study of the phenomenon of intermittent left bundle branch block has been presented. We tested a variety of physiologic maneuvers and pharmacologic agents for their effects on intraventricular conduction. The data indicated that heart rate could not have been the primary determinant of the type of intraventricular conduction, but may have had a secondary or modifying influence. Carotid sinus pressure was shown to both terminate and induce bundle branch block. The form of the ventricular complex during carotid sinus pressure was related to the degree of prolongation of the R-R interval. It could not be determined from our data whether the response to increased vagal tone was due to direct inhibitory effect of the vagus or to other factors, such as the marked fall in mean arterial blood pressure. The effects of the various physiologic maneuvers suggest that hemodynamic factors may play a major role in determining the form of the ventricular complex. The responses to the various pharmacologic agents tested seemed to indicate that the diseased bundle was extremely sensitive to influences primarily altering intraventricular conductivity. In conclusion, after a careful analysis of studies performed on a patient with intermittent left bundle branch block, we still do not know which factor(s) was (were) most important in governing the mode of intraventricular conduction. It appears that heart rate can be eliminated as a primary factor in this patient. Perhaps the final answer to this problem lies in a better understanding of the interaction of hemodynamic, neural, and nutritional factors on intraventricular conduction.

The light microscopic demonstration of hydroperoxidase-positive Phi bodies and rods in leukocytes in acute myeloid leukemia.

SummaryUnique fusiform or spindle-shaped particles (Phi bodies) and rods with hydroperoxidase (catalase and/or peroxidase) activity are present in human granulocyte precursors only in acute myelogenous leukemia (AML). These newly recognized particles are much more numerous and prominent than Auer rods. They may be rapidly and readily identified using the microscope in marrow or peripheral blood films when the procedures recommended in this paper for fixation, incubation for hydroperoxidase demonstration in 3,3′-diaminobenzidine (DAB)/H2O2 medium, copper salt treatment and counterstaining (optional) with the Papanicolaou method are employed. Films prepared in the same manner but treated with benzidine/H2O2 medium for myeloperoxidase did not reveal these particles.We believe that Phi bodies are pathognomonic of AML since they are almost invariably present in AML patients with active disease. Their presence serves to distinguish AML from acute lymphocytic leukemia and from chronic granulocytic leukemia in blast crisis. Since the particles disappear in disease remission and reappear upon relapse, the recommended procedure is not only useful in diagnosis but in guiding therapy.When a very rapid diagnosis is needed, it is not necessary to counterstain the preparations, but the nuclei, cytoplasm and plasmalemma can readily be observed in the granulocyte precursors when they are counterstained by the Papanicolaou method. This treatment does not diminish the clarity of the Phi bodies and rods which stain by virtue of their peroxidatic activity.This cytochemical diagnostic procedure should be considered for adoption by hematology laboratories.

Influence of trauma on the unusual distribution of metastases from carcinoma of the larynx

A patient is described with carcinoma of the larynx, locally irradiated and “cured” without evidence of distant metastases. Concomitant with the radiation treatment, he sustained trauma to certain areas of the body as a result of the application of a spica cast and crutch ambulation. Subsequently, metastases developed in areas of the skin, bone, and lymph nodes which had been previously traumatized. The unusual distribution of metastases is discussed with respect to the role of trauma in determining the localization of metastatic lesions, and the implications of the delay in the appearance of metastases following “cure” of a primary lesion are considered.