Sternberg-Reed Cells in the Peripheral Blood of Patients with Hodgkin's Disease

Our observations of 135 patients indicate that 37 per cent of those sufferingfrom Hodgkin’s disease exhibit abnormal cells in the leukocyte concentrates ofthe peripheral blood during the course of their illness. Typical Sternberg-Reedcells were found in 18.5 per cent of patients and were present only in theadvanced stages of generalized Hodgkin’s disease.

The presence of Sternberg-Reed cells in the peripheral blood indicates anadvanced stage of the disease but does not necessarily predict an immediatelyfatal outcome.

Comparative studies, searching for Sternberg-Reed cells in the splenic circulation, showed no Sternberg-Reed cells to be present in the splenic arteries ofpatients with Hodgkin’s disease; but numerous Sternberg-Reed cells were present in the splenic vein, particularly after mechanical squeezing of the spleen.A possible hypothesis is given to support the evidence for the circulation ofSternberg-Reed cells and an explanation for their lower incidence in the peripheral blood.

Our observations support the hematogenous metastasis of Hodgkin’s disease.

Submitted on June 2, 1965 Accepted on August 2, 1965     

Hodgkin''s disease; mortality in the United States, 1921-1951; race,sex and age distribution; comparison with leukemia

Mortality from Hodgkin’s disease in the United States during the period1921 through 1951 was analyzed with respect to race, sex and age incidence anddistribution. The findings were compared with those reported for leukemia.

The recorded death rate from Hodgkin’s disease rose from 6.9 in 1921 to 17.0per million in 1951. During this period, the death rate from leukemia rose from14 to 61 per million.

The death rate among males is higher than among females for both diseases;the male predominance is more marked in Hodgkin’s disease than in leukemia.The rate is higher among whites than non-whites for both diseases; the whitepredominance is more marked in leukemia than in Hodgkin’s disease. There isno peak in rate during childhood for Hodgkin’s disease as there is for leukemia,and the increase in rate with age is much less steep for Hodgkin’s disease than forleukemia.

The mean age at death of adults dying from Hodgkin’s disease and from leukemia increased by 3.5 and 8.0 years, respectively, between 1925 and 1950.The male-female sex ratio for Hodgkin’s disease decreased slightly, and increasedslightly for leukemia between 1925 and 1950.

Submitted on July 13, 1955 Accepted on September 12, 1955     

Behavior of total serum complement in Hodgkin''s disease and other malignant lymphomas

Using the method of Mayer and collaborators for the determination ofcomplement in the blood serum, 67 normal persons, 72 patients with Hodgkin’s disease, 28 with other types of lymphoma and 65 with cancer involvement of various organs were studied.

Fifty-eight of 72 Hodgkin’s disease patients were found to have an elevatedlevel of complement, 12 a normal level and 2 a below-normal level. Elevatedlevels were found also in patients with other lymphomas and cancer.

An association between elevated complement, increased sedimentationlevel, decreased serum properdin, positive C-reactive protein and elevatedbeta globulin in the serum was noted.

The conclusion reached is that an elevation of complement in the serumindicates that Hodgkin’s disease is in an active phase. As to the nature ofthe disease, the statistics assembled seem to give no clue.

Submitted on March 7, 1958 Accepted on July 22, 1958     

The Rh chromosome frequencies in England

The results are reported of testing 1073 English bloods with the Rh antibodiesanti-C, anti-C^w, anti-c, anti-D, anti-E and anti-e. The results of another series of927 bloods, already published, are here reproduced. The total of 2000 bloods hasbeen used by Fisher to estimate, by his method of maximum likelihood, the Rhchromosome frequencies in England. The estimates are: CDe 40.75 per cent, cde38.86 per cent, cDE 14.11 per cent, cDe 2.57 percent, C^wDe 1.29 per cent, cdE 1.19per cent, Cde 0.98 per cent, and CDE 0.24 per cent.

A brief account is given of the three pairs of alternative antigens shown byFisher to be the basis of the Rh blood groups. Fisher’s interpretation must now beconsidered as established beyond doubt. A possible genetic basis of these relatedantigens is discussed.

Note: ACKNOWLEDGMENTSWe are deeply indebted to Professor Fisher for many reasons, but we should particularly like toacknowledge his kindness in allowing us to publish the results of his calculations of the chromosomefrequencies.For the antisera used in the investigations we are indebted to the following: Doctors E. F. Aubert,Sheila Callender, D. S. Dick, R. J. Drummond, Mr. I. Dunsford, Doctors A. J. McCall, Brenda Morrison,J. Murray, E. Wordley and R. A. Zeitlin.We also thank Dr. H. F. Brewer of the London Red Cross Blood Donor Service, and Dr. J. F. Loutit ofthe National Transfusion Service, for providing us with large numbers of blood samples.We also wish to acknowledge the assistance of Dr. Marjory N. McFarlane in the earlier part of thisinvestigation.

     

Phase microscopy studies of Hodgkin's disease lymph nodes in relation to histogenesis of the Sternberg-Reed cell

1. The free reticulum cell in Hodgkin’s disease undergoes progressive cytologicalterations leading to the formation of Sternberg-Reed cells.

2. The other free cellular components of Hodgkin’s disease nodes are cytologically normal.

     

Hypoprothrombinemia; studies of a case of the idiopathic type and the effect of serum administration

1. The reported cases of idiopathic hypoprothrombinemia are reviewed briefly,and a case observed for over three years is presented. Particular attention is calledto the similar clinical pattern presented by the chronic cases.

2. Studies are presented indicating that in this patient the delay in prothrombintime was due, at least in part, to a deficiency of a factor necessary for rapid conversion of prothrombin. This factor, or factors, which we have called Ac-globulin,is contained in a highly active state in fresh normal serum.

3. After the in vitro demonstration of a deficiency of Ac-globulin in the patient’sblood, it was possible to bring about a marked reduction in the patient’s prothrombin time by the intravenous administration of relatively small amounts (15 to45 cc.) of fresh normal (thrombin-free) serum. A further reduction of the prothrombin time to near normal values was brought about by combined wholeblood and serum administration. The evidence suggests that partial correction ofboth prothrombin and Ac-globulin deficiency respectively resulted from suchtherapy.

4. The possible effects of serum and whole blood upon the delayed prothrombinconversion rate of dicoumarolization and liver disease are discussed and preliminary observations in the former type suggest that such therapy may be useful.

Note: ACKNOWLEDGMENTSWe wish to express our appreciation to the following for their cooperation in this study:Dr. McLemore Birdsong, Associate Professor of Pediatrics, University of Virginia Medical School;The Department of Pediatrics, University of Virginia Hospital; The Department of Biochemistry, University of Virginia Medical School; Dr. Myers H. Hicks, Assistant Resident in Medicine, Universityof Virginia Hospital; Dr. Walter H. Seegers, Professor of Physiology, Wayne University College ofMedicine.

     

The Histochemical Study of Zinc Content in Granulocytes in Normal Adults and in Hematologic Disorders

Zinc in granulocytes was determined using a dithizone histochemicalmethod. Investigations were performed in both bone marrow and in peripheralblood from ten healthy adults and in 62 patients with various hematologicdisorders. In bone marrow, zinc appears in metamyelocytes. The amount increases with maturation. In the granulocytes of peripheral blood, zinc valuesare about 30 per cent higher than in bone marrow.

Zinc is significantly decreased in granulocytes in chronic granulocytic leukemia, acute myeloblastic leukemia, multiple myeloma and Hodgkin’s andincreased in chronic lymphocytic leukemia and osteomyelosclerosis.

Submitted on September 16, 1963 Accepted on April 27, 1964     

The mechanism of the anemia associated with Hodgkin''s disease

1. The survival of autotransfused Cr⁵¹-tagged erythrocytes was shortenedin a group of five patients with the anemia of Hodgkin’s disease, but since thenormal marrow is believed to be capable of compensating for destruction ratesof six to eight times greater than normal, it is felt that the increased rate ofhemolysis was not sufficient to account for the development of anemia in anyof these patients.

2. There was evidence of an increased rate of erythropoiesis in all of thepatients with Hodgkin’s disease. This was manifested by normoblastic hyperplasia of the marrow, a moderate reticulocytosis and increased plasma ironclearance rates. The shortened red cell survival times were associated withthe increased plasma iron clearance rates. However, in view of the fact thatall of the patients were anemic, it is evident that these patients were incapableof increasing the rate of red cell production sufficiently to compensate for theincreased rate of destruction.

3. Intravenously injected Fe⁵⁹ citrate was incorporated more rapidly intothe circulating red cell mass in the patients with Hodgkin’s disease than inthe normal subjects.

4. The tissue iron stores of the liver and spleen were greatly increased,but no iron was demonstrated in the marrow of a group of seven patientswith Hodgkin’s disease.

5. The plasma iron was low and the UIBC normal in a group of 12 patientswith active Hodgkin’s disease.

6. It is suggested that one of the factors which limits the ability of themarrow to produce hemoglobin in the anemia of Hodgkin’s disease may be arelative hypoferremia caused by a defect in the mobilization of iron from tissuestores.

Submitted on April 17, 1958 Accepted on February 2, 1959     

Editorial: Lymphocytopenia in Hodgkin's Disease

The lymphocytopenia of Hodgkin’s disease has been reviewed in the lightof recent knowledge of lymphocyte function. It is suggested that the anergyof early Hodgkin’s disease is a peripheral defect—a manifestation of abnormal lymphocyte function. Later in the course of the condition profoundlymphocytopenia develops and most probably contributes to the more severeimmunologic deficiencies of advanced Hodgkin’s disease.

Submitted on November 2, 1964 Accepted on February 14, 1965     

Effects of the intramuscular administration of BAL in a subject with the sickle cell trait; case report

The effects of the intramuscular administration of BAL in a Negro harboringthe sickle cell trait have been presented. It was observed that the rate of sicklingwas accelerated and the erythrocyte sedimentation rate was retarded in the presenceof BAL both in vitro and apparently in vivo. However, the administration ofBAL produced none of the pathologic sequelae characteristic of sickle cell disease.

Note: ACKNOWLEDGMENTI wish to thank Dr. M. M. Wintrobe, Professor and Head of the Department of Medicine, Universityof Utah College of Medicine for his numerous invaluable suggestions and criticisms.

     

The genetic relation and clinical differentiation of Cooley's anemia and Cooley's trait

1. Four additional families illustrating the clinical and genetic relationshipsof Cooley’s anemia and Cooley’s trait have been presented.

2. Blood findings in an offspring of a patient with Cooley’s anemia are recorded.

3. The asymptomatic nature of Cooley’s trait and its differentiation fromCooley’s anemia has been emphasized.

4. The inheritance of Cooley’s trait and Cooley’s anemia may be best explainedin terms of an incomplete dominant or of the simultaneous appearance of twononallelomorphic genes.

Note: ACKNOWLEDGMENTWe are indebted to Dr. John H. Linner for many of the observations on the Ca family and to MissClara Gillette for observations on the Cr family.

     

The Effects of Two Alkaloids Derived from Vinca Rosea on the Malignant Cells of Hodgkin's Disease, Lymphosarcoma and Acute Leukemia in Vivo

Hodgkin’s disease, lymphosarcoma, and acute leukemia have been studiedafter treatment with the Vinca rosea alkaloids (vinblastine and vincristine), inorder to demonstrate and evaluate the mitosis-arresting effects of the twodrugs on the malignant cells. Histologic sections, lymph node and bone marrow aspirations were performed immediately before and 24 hours after theintravenous administration of the drugs in 15 cases of Hodgkin’s disease, 12 oflymphoblastic lymphosarcoma, and 12 of acute leukemia, besides other miscellaneous cases.

In Hodgkin’s disease aspirates and sections showed a clear-cut metaphasearrest in the post-VLB specimens, chiefly affecting the pre-Sternberg or Hodgkin cells. This effect, besides corroborating the fundamentally stathmokineticmechanism of VLB in Hodgkin’s disease, was considered an additional factorin confirming the widely proposed conception that these cells represent thefundamentally proliferating and malignant tissue of this disease.

In the acute leukemias and lymphoblastosarcomas, cytomorphologic andquantitative studies demonstrated that the oncolytic effects correlated wellwith the magnitude of metaphasic blockade. It is postulated that only activelyproliferating cells—the so-called "growth fraction"—are the target for thesealkaloids.

Submitted on January 30, 1966 Accepted on June 26, 1966     

THE USE OF PHOTO-ELECTRIC TURBIDOMETRY IN THE DETERMINATION OF RED CELL COUNTS, HEMATOCRITS, AND HEMOGLOBIN

1. Blood turbidometry is recommended as a screening technic for distinguishingbetween anemic and nonanemic individuals.

2. Blood turbidometry must be supplemented by other technics for an exactdiagnosis of the type of anemia. However, with such help it makes its own contribution to the accuracy of the diagnosis.

3. Blood turbidometry alone would seem to be capable of following an anemicindividual’s response to therapy once the proper diagnosis is established.

4. Determination of hemoglobin concentration by turbidometry appears as adistinct possibility. However, further investigation is necessary to validate itsutility.

5. Evidence is accumulated that the shadow-volume relationship is a constantin several species.

Note: The author is particularly indebted to the following for advice in connection with this work: Dr.Peter Olafson of the Department of Veterinary Pathology, Dr. C. E. Hayden of the Department of Veterinary Physiology, Dr. L. I. Barnes of the Department of Physics, and Dr. W. B. Carver of the Department of Mathematics, all of Cornell University, and Dr. Charles P. Winsor of Johns Hopkins University.Dr. Robert N. Ericson conducted some preliminary explorations of the problem with the authorwhen both were connected with Kansas State College.

     

Nitrogen mustard therapy in Hodgkin's disease; analysis of 50 consecutive cases

1. Methyl bis (B chloroethyl) amine (HN₂) was given by intravenous route forthe treatment of 50 successive cases of Hodgkin’s disease, most of them severeand far advanced. Doses somewhat smaller than the usually recommended amountof 0.1 mg. per Kg. were used in courses of four to six injections.

2. Nausea and vomiting followed administration of the drug in 93.2 per centof cases. Chills and fever occurred in 12.4 and 6.8 per cent of cases respectively.Dyspnea, cyanosis and diarrhea were rare.

3. In previously untreated cases, remissions were of much shorter duration thanthose obtained with Roentgen therapy. However, striking remissions were commonly obtained in x-ray resistant cases. Remissions lasted from 17 to 331 days andin individuals receiving multiple courses were roughly proportional to the totaldosage administered. A moderate prolongation of the remission period was obtained when HN₂ was combined with roentgen therapy.

4. Constitutional symptoms such as fever, night sweats, weakness and itchingresponded exceedingly well in most cases to HN₂ therapy. Many previously incapacitated patients were completely rehabilitated for several weeks to severalmonths after a single course of HN₂ therapy.

5. Adenopathy and splenomegaly regressed in 70.2 and 71.7 per cent of casesrespectively. Lymphoid masses previously resistant to x-ray therapy appeared todevelop increased sensitivity to x-rays after a course of HN₂ therapy.

6. Patients with extensive mediastinal involvement and obstructive symptomsresponded only moderately well while those with lesser degrees of involvementshowed a better response.

7. Paraplegia due to intraspinal involvement was partially relieved in half thecases while pain due to similar involvement was dramatically relieved in all cases.Pain due to pressure upon peripheral nerves was similarly relieved in all cases.

8. A slight but definite fall in the erythrocyte and hemoglobin levels occurredwithin five to six days after the institution of therapy. Reticulocytes were maximally depressed on the sixth to tenth days. Of the leukocytic elements, the granulocytes were predominately affected, with maximal cytopenic levels on thetwenty-first to twenty-fifth day. The leukocytes gradually returned to normal bythe thirty-sixth to fortieth day. Cases presenting an initial leukopenia tendedto develop normal leukocyte counts after an initial drop to low levels. The plateletcount was affected in only 20.5 per cent of cases. Terminal cases at times developedmarked pancytopenia.

9. In one case severe hemorrhagic complications due chiefly to thrombocytopeniafollowed the administration of the tris form of nitrogen mustard and graduallysubsided after a very stormy course.

10. Progressive but temporary marrow hypoplasia followed nitrogen mustardtherapy in eleven cases studied with serial marrow punctures. Erythroblastic depression was noted within twenty-four hours and granulocytic depression withinforty-eight to seventy-two hours. The megakaryocytes proved to be the most resistant of the marrow elements. The marrow picture usually returned to normalspontaneously within a period of six to eight weeks after the cessation of therapy.

11. Lymph node punctures revealed degeneration and pyknosis of lymphocyteswithin twenty-four hours after the institution of therapy with a subsequent gradual disappearance of polymorphonuclear neutrophiles, eosinophiles, plasma cells,reticulum cells and Dorothy Reed cells. Miliary foci of necrosis were demonstratedin a gland obtained at post mortem seven days after the institution of HN₂ therapy.

12. Miliary foci of necrosis were demonstrated in the liver of 3 cases dying between nine and nineteen days after the institution of HN₂ therapy. No such findingscould be found in a case in which death occurred fifty-four days after the initiationof therapy.

13. The therapeutic results with HN₂ in Hodgkin’s disease appeared to havelittle relationship to the histologic appearance of the involved tissue. The immediate response in so-called Hodgkin’s sarcoma was particularly striking, and in onecase, a remission lasting about a year took place.

     

Report of a Three-Year Study of Red Cell Mobility and the Slowing Factor in Serum of Persons with Lymphoma

1) A variety of pathologic conditions retard the electrophoretic mobilityof the red blood cell.

2) Two retarding factors have been found in the blood serum, one that reduces the mobility of the red cell from normal (1.33µ/cm./sec./volt) to 0.89µand one that reduces it to 1.14µ.

3) The "0.89" factor and the "1.14" factor can be differentiated and identified.

4) The 0.89-factor has been found in the serum of 99 per cent of patientswith cancer and Hodgkin’s disease studied and has been lacking from theserum of all persons with benign tumor.

5) The 0.89-factor has also been found in patients with infectious mononucleosis.

6) A few physical characteristics that enable differentiation of the two slowing factors are described.

7) Clarification of the role played by the 0.89-factor in malignant neoplasmis deemed important.

8) Determination of the presence or absence of the 0.89-factor in the bloodserum may become of value in differential diagnosis of malignant neoplasm.

Submitted on May 4, 1962 Accepted on July 18, 1962     

Splenectomy in far-advanced Hodgkin''s disease; report of five cases

Five patients with far-advanced Hodgkin’s disease and with evidence of hematopoietic failure were treated by splenectomy in order to determine whether: (1)the course of the disease could be modified, (2) the hematologic picture improved,and (3) responsiveness to nitrogen mustard or x-ray therapy restored. These patients showed a transient slight improvement in their hematologic status, butthe course of the disease possibly was accelerated, and the patients all diedwithin thirteen weeks, without showing renewed suitability or increased responsiveness to therapy.

On the basis of our data and a review of thirty cases from the literature, it isconcluded that splenectomy is not a useful procedure its Hodgkin’s disease, exceptfor certain specific indications. These may be: (1) an apparently solitary splenictumor; (2) acquired hemolytic anemia, although this process may be better controlled in some cases by treating the underlying Hodgkin’s disease with x-rays,nitrogen mustard, or triethylene melamine ; (3) thrombocytopenic purpura,which appears to be more profound than is to be expected from the severity andextent of Hodgkin’s disease; and (4) hypersplenism. Hematopoietic depressionin the vast majority of patients with Hodgkin’s disease, however, cannot beattributed to splenic overactivity or malfunction.

Submitted on October 23, 1953 Accepted on December 17, 1953     

Preservation of normal human plasma in the liquid state; clinical,chemical, and physicochemical studies during three years of storage at room temperature

1. During preservation of human plasma in the liquid state at room temperaturefor three years, the alpha-amino nitrogen and the nitrogen content of the tungsticacid filtrate rise slowly until about two years have elapsed, after which time theselevels do not increase significantly.

2. During the entire period of storage the nitrogen contents of the trichlor-acetic acid filtrate and the "polypeptide index" increase progressively. Theactual increase represents hydrolysis to nonprotein size of 3 to 4 per cent of theoriginal protein.

3. The colloid osmotic pressure of stored plasma is slightly but significantlygreater than that of fresh plasma.

4. The viscosity of stored plasma is slightly but significantly greater than thatof fresh plasma.

5. The electrophoretic patterns of stored plasma show increases of alpha globulin and albumin concentration, complete disappearance of gamma globulin(containing immune properties) and fibrinogen, and some reduction of beta globulin concentration as compared to fresh plasma.

6. Analysis of 3,384 questionnaires completed after administration of liquidplasma more than a year old indicates that the transfusion of such plasma continues to be safe and beneficial up to at least three years of storage. The untowardreaction rate following these administrations was significantly less than thatfollowing a comparable series of 1500 administrations of commercially prepareddried plasma.

Note: The technical assistance of R. L. Erickson, PhM1c, V6, U.S.N.R., and P. Livingood, PhM3c, V6, U.S.N.R., is gratefully acknowledged. The kindness of Dr.Ellice McDonald, Director, Biochemical Research Foundation, in arranging for theelectrophoretic work and in permitting the reporting of the work here is appreciated with deep thanks.This study was possible only with the close cooperation of the Blood and PlasmaDepartment, Naval Medical School. For this cooperation, the authors are considerably indebted to Commander S. T. Gibson, M.C., U.S.N.R., LieutenantCommander H. R. Evans, (HC), U.S.N., and Lieutenant Commander M. T. Sproul,H(W), U.S.N.R.

     

Demonstration by the Nadi reaction of cytochrome oxidase activity in cells of the lymphoid and myeloid series obtained from normal individuals and patients suffering from Hodgkin's and other diseases

Using the Nadi reaction, cytochemical studies of the cytochrome oxidaseactivity of cells of lymphoid and myeloid tissue were carried out. Normal cellsand those from patients with Hodgkin’s disease and leukemia were examined.

With the exception of monocytes and macrophages cells from lymph nodes,spleen, bone marrow and peripheral blood show a low level of cytochromeactivity when compared with myocardial, liver and renal tubular epithelium.

Leukemic cells and those from lymph nodes affected by Hodgkin’s diseasecontain about the same degree of cytochrome activity as their normal counterparts, under the conditions of this study.

The cytoplasmic particles stained by the Nadi reaction correspond in size,distribution and number to particles which can be stained supravitally by janusgreen.

Submitted on March 2, 1951 Accepted on April 18, 1951     

Phytohemagglutinin-induced Lymphocyte Transformation: The Relationship to Prognosis of Hodgkin's Disease

Forty-three untreated patients withHodgkin’s disease were evaluated between 1965 and 1967 with PHA-stimulated peripheral leukocyte cultures. Nocorrelation was found between PHA-induced lymphocyte transformation atthe time of diagnosis and the clinicalcourse of the patient’s Hodgkin’s disease. There is also no correlation between lymphocyte transformation andthe histologic pattern of nodular sclerosis. Although PHA-induced lymphocyte transformation appears to be ageneral index of immunologic status,it has not proven of value as a prognostic sign in Hodgkin’s disease.

Submitted on September 22, 1971 Revised on October 26, 1971 Accepted on October 28, 1971     

STUDIES ON THE PHYSIOLOGY OF THE WHITE BLOOD CELL: THE GLYCOGEN CONTENT OF LEUKOCYTES IN LEUKEMIA AND POLYCYTHEMIA

The technic of determining glycogen in isolated white blood cells was appliedto the study of the different types of leukemia and of polycythemia, in order toobtain information on the physiology of the white blood cell. From this study itis concluded that the granulated leukocyte is the only carrier of glycogen in wholeblood. The "reducing substances" in lymphocytes and blast cells are not consideredas true glycogen.

The glycogen content of wet white blood cells in the rabbit amounts to about1 per cent. In the human being a range of from 0.17 to 0.67 per cent was calculated.In disease higher percentages occur, in polycythemia up to 1.64 per cent and inglycogen storage disease up to 3.05 per cent.

The glycogen concentration of normal white blood cells is within the same rangeas that of the striated muscle.

Note: I acknowledge with gratitude my indebtedness to Dr. William Dameshek for giving me the opportunity of analyzing the blood of some of the patients studied. Miss M. H. Campbell, Miss H. A. Clark,and Miss L. M. Garofalo have aided in carrying out many of the blood counts.