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BACKGROUND Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil plus vincristine and prednisone (CMFVP) was compared with single-agent L-phenylalanine mustard (L-PAM) for the treatment of patients with axillary lymph node positive primary breast carcinoma over 20-years of follow-up. METHODS Four hundred forty-one women with axillary lymph node positive breast carcinoma were randomized to receive either combination chemotherapy with cyclophosphamide (60 mg/m2 orally every day for 1 year), fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year), methotrexate (15 mg/m2 IV weekly for 1 year), vincristine (0.625 mg/m2 IV for 10 weeks), prednisone (30 mg/m2 orally on Days 1–14, 20 mg/m2 on Days 15–28, and 10 mg/m2 on Days 29–42), or single-agent chemotherapy with L-PAM (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) after undergoing surgery. Patients were stratified according to menopausal status and number of positive lymph nodes (1–3 positive lymph nodes or > 3 positive lymph nodes). Seventy-seven patients were ineligible. RESULTS The maximum follow-up is 24 years, with a median follow-up of 21.5 years. Disease free survival and overall survival were superior with CMFVP (two-sided log-rank test; P = 0.0008 and P = 0.007, respectively). For all patients, the estimated 20-year survival rate of patients who received CMFVP was 40% compared with 27% for patients who received L-PAM. There was a substantial survival benefit for CMFVP compared with L-PAM in the subsets of premenopausal patients and patients with four or more positive lymph nodes. The estimated 20-year survival rate for premenopausal women who received CMFVP was 49% compared with 33% for premenopausal women who received L-PAM. Among women with ≥ 4 positive lymph nodes, the estimated survival rate for patients who received CMFVP was 31% compared with 15% for patients who received L-PAM. Both regimens were tolerated well. Toxicity was more severe and frequent among patients who received CMFVP. CONCLUSIONS The authors conclude that, after 20 years of follow-up, adjuvant chemotherapy with CMFVP remains superior to L-PAM for the treatment of patients with lymph node positive breast carcinoma. Cancer 2003;97:21–9. © 2003 American Cancer Society. DOI 10.1002/cncr.10982

Fifty-eight evaluable patients with acute leukemia were treated with Mitoxantrone (DHAD) according to two schedules: 14 mg/M2 as a single I.V. pulse dose administered three-week intervals, and 4 mg/M2/day for five days every three weeks. Six of 58 patients achieved a complete remission. One complete remission and 1 partial remission were observed among 26 patients treated with the single pulse schedule. Five (16%) complete remissions were attained among 32 patients treated on the daily × 5 schedule. Responses were observed only in patients with non-lymphoblastic leukemia. DHAD was very well tolerated with myelosuppression as the major toxicity. Nausea and vomiting were minimal. Subclinical cardiac toxicity occurred in two patients. This was identified by serial reductions in cardiac ejection fractions. DHAD appears to have significant activity in acute non-lymphoblastic leukemia with minimal toxicity.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP to two years of intermittent L-PAM in women with operable breast cancer with histologically positive axillary lymph nodes. In fully evaluable patients with a 42-month median and 30-month minimum follow-up, treatment failures have occurred in 26% of 145 receiving CMFVP and 47% of 167 women given L-PAM (P = 0.002). Disease-free survival times were significantly longer with CMFVP than with L-PAM in the following subgroups: premenopausal women (P = 0.002), postmenopausal women (P = 0.002), women with 1-3 involved axillary nodes (P = 0.003), and women with four or more involved axillary nodes (P = 0.002). CMFVP was effective in pre- and postmenopausal women. There is a significant difference in survival in favor of CMFVP compared to L-PAM (P = 0.005). The life table estimates of survival at 42 months are 86% for women on the CMFVP treatment arm and 73% for women on the L-PAM treatment arm. There was no correlation between the interval from mastectomy to onset of chemotherapy (between one and six weeks) and recurrence rates. Acute toxicity with both treatment arms was moderate and reversible. These results show that continuous CMFVP is superior to intermittent L-PAM in decreasing recurrences and increasing survival in both pre- and postmenopausal women with operable breast cancer with histologically involved axillary nodes.

The SWOG carried out a Phase II evaluation of rubidazone in patients with advanced breast cancer. Good risk patients were given rubidazone 150 mg/m2 IV every three weeks. Poor risk patients were given a 25% dose reduction at the start of treatment. Rubidazone dose was increased or decreased depending on toxicity. One patient went into complete remission, four had partial remission and nine had stable disease. Forty-two patients showed increased disease on treatment. No cardiotoxicity was seen, but other common toxicities noted included mostly mild to moderate myelosuppression, nausea, vomiting and alopecia. This study failed to indicate significant antitumor activity of rubidazone in patients with advanced breast carcinoma.

The Southwest Oncology Group in a prospective randomized study compared one year of adjuvant combination chemotherapy with continuous CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) to two years of intermittent L-phenylalanine mustard (L-PAM) in women with operable breast cancer with histologically positive axillary lymph nodes. In fully and partially evaluable patients with a 68-month median follow-up, treatment failures have occurred in 27% of 172 receiving CMFVP and 47% of 186 women given L-PAM (p = 0.002). The advantage for women receiving CMFVP was seen for all subsets regardless of menopausal status except among women who were premenopausal and had 1-3 positive nodes. Based on this study, a second study was implemented using both the estrogen-receptor (ER) content of the primary tumor and axillary nodal status to select therapy.

SummaryThis study was designed to determine whether inflammatory granulocytes are derived solely from the blood or from a hypothetical extramedullary tissue pool of granulocytes, in addition to the blood. Blood granulocytes were labeled in vitro with DFP32, infused, and their subsequent appearance in induced inflammatory exudates studied. From a comparison of the maximum blood granulocyte specific activity and the exudate granulocyte specific activity it was evident that at least three-fourths of the exudate neutrophils were derived directly from the blood. To determine if more than three-fourths of the exudate neutrophils were from the blood the proportion of granulocytes in an exudate 4 hours old which had left the blood during each of the preceding 4 hours was calculated. It was found that approximately 36% of the granulocytes in a 4 hour exudate had left the blood during the first hour of inflammation. The figures for the 2nd, 3rd and 4th hours of inflammation were, respectively, 32%, 25% and 9%, maki...

The kinetics of blood neutrophils was investigated by means of the in vitro radioactive diisopropyl fluorophosphate method in 35 patients with a chronic, steady-state neutropenia. There were 17 patients in whom the half disappearance time of neutrophils was normal. In 10 of these patients, the production of neutrophils was low and in 7, production was normal. In 18 patients the half disappearance time of neutrophilic granulocytes was shorter than normal. The production of neutrophilic granulocytes was low in five of these patients, normal in eight patients, and increased in five. An attempt was made to correlate other laboratory measurements with the kinetic picture, but no relationship was found; the marrow neutrophil reserve as measured by endotoxin or cortisol injection; marrow cellularity on aspiration or biopsy; in vitro-labeling index with 3HTdR; or serum lysozyme concentration proved of no value in identifying the various kinetic groups. The only finding that seemed to correlate with the kinetic picture was the presence or absence of splenomegaly. In 12 of the 18 patients with a short half disappearance time, splenomegaly was present whereas in 15 of 17 patients with a normal half disappearance time, there was no splenomegaly. Of 20 patients with greater than 1000 neutrophils per mm3, 17 were found to have a normal total-blood neutrophil pool. Thus these patients, with many of their cells marginated, agree to have a “shift neutropenia.” Myelocyte to blood transit time and myelocyte generation time, as measured in seven patients by in vivo labeling with diisopropy fluorophosphate, proved to be essentially normal. Thus, it appears that in chronic neutropenia, increased or decreased production of neutrophils is accomplished by increasing or decreasing early precursor input into the system.

Ferrokinetic studies were performed in three copper-deficient swine and the results have been compared with similar studies in 18 normal pigs. The mean value for the plasma iron turnover rate in the deficient swine was 1.76 mg./kg. day; for the red cell iron incorporation rate, 1.24 mg./kg. day; for the red cell iron turnover rate, 1.18 mg./kg. day; for the red cell life span, 13 days. Corresponding figures in the normal swine were 1.11 mg./kg. day, 1.01 mg./kg. day, 0.59 mg./kg. day and 63 days, respectively. The red cell life span was measured by the use of radioactive chromium in a total of 26 pigs. The mean erythrocyte half-life of normal cells transfused into normal pigs was 17 days. The mean half-life of erythrocytes from copperdeficient swine transfused into copper-deficient swine was 9 days. The mean half-life of red cells from control animals transfused into copper-deficient swine was 16 days while that of erythrocytes from copper-deficient swine transfused into normal pigs, was 13 days. The mean half-life of cells from iron-deficient pigs transfused into iron-deficient pigs was 19 days. It is concluded that copper deficiency anemia results from both a shortened erythrocyte survival time and limited capacity of the bone marrow to produce red cells. It is suggested that copper is an essential component of erythrocytes in swine.

SummaryDogs were given nitrogen mustard (HN2) and radioactive diisopropylfluo-rophosphate (DFP32) and the type of neutropenia which developed, whether of “early” or “late” onset, was correlated with changes observed in the blood granulocyte specific activity (BGSA) curve. The duration of phase X+II of the BGSA curve measures the time required for the storage pool of the marrow to empty by releasing cells to the blood. In dogs developing “late” onset neutropenia there was an abnormally short phase I+II while in those developing “early” onset neutropenia phase I+II was normal. These results were compared with those reported previously in vinblastine sulfate treated dogs. It was concluded that dogs with “early” onset neutropenia after HN2 must have developed a defect leading to an abnormally low rate of output cells from the marrow granulocyte reserve (MGR) to the blood. Reduced output developed despite the presence of enough cells in the MGR to maintain a normal rate of output.

Absolute blood leukocyte counts were determined in 291 normal individuals (226 Caucasian and 65 Negro), using modern, electronic leukocyte counting methods. Two hundred cell differential counts of coverslip smears stained with Wright’s stain were done. Normal mean values and 95% limits expressed as cells per cu. mm. were: band neutrophils 500 (100 to 2,100); segmented neutrophils 3,000 (1,100 to 6,050); total neutrophils 3,650 (1,830 to 7,250); lymphocytes 2,500 (1,500 to 4,000); monocytes 430 (200 to 950); eosinophils 150 (0 to 700); basophils 30 (0 to 150). No clinically significant differences between Negroes and Caucasians were found.

Summary1. Twenty-three swine were fed a diet deficient in lysine. In addition, 5 swine were given hexahomoserine (6-hydroxy-DL-norleucine), a lysine antagonist. 2. All animals developed a normocytic, normochromic anemia, which was accompanied by hypoalbuminemia and hypocupremia. No alterations from the normal were noted in the plasma iron concentration or in bone marrow morphology. The anemia responded rapidly to administration of lysine. 3. The data presented indicate that lysine is essential for normal erythropoiesis in swine.

A technic for the in vitro labeling of human platelets with DFP32 is presented, critically evaluated, and compared to in vivo methods employing DFP32 and to in vitro methods using Cr51. The initial recovery of platelets labeled in vitro with DFP32 averaged 79 per cent, but the survival curve was characterized by an irreversible initial loss of platelet radioactivity. Experiments in which platelets were simultaneously labeled in vitro with both DFP32 and Cr51 suggest that this is not due to elution of DFP32. The survival curve of platelets labeled in vivo with DFP32 shows an initial transient reduction in platelet radioactivity. It is suggested that both of these aberrations in initial survival are the result of platelet injury by DFP32. Significant "tailing" was observed in the survival curves obtained with DFP32, and possible explanations of this phenomenon are discussed. DFP32-labeled platelets circulating after 5 hours apparently survive normally and disappear from the circulation as a rectilinear function over the next 6-8 days. Although both in vitro and in vivo labeling methods employing DFP32 provide a meaningful approximation of platelet lifespan, the initial and terminal aberrations of the survival curves greatly complicate further interpretation. Dextran had no detectable effect on platelet survival, and epinephrine, Mecholyl, and cutaneous vasodilatation did not alter the platelet count or the specific activity of circulating labeling platelets in human subjects. The problem of initial platelet survival and the question of an extravascular or marginal platelet pool is discussed in the light of these data.

To test the hypothesis that there is normally a 14-21 day cycle in blood neutrophil concentration, the blood of 13 normal male volunteers was sampled daily for 42 consecutive days. No evidence for cyclic variation in neutrophil concentration was found. The effect of deleting four samples per week and interpolating values linearly or parabolically was tested by power spectrum analysis, since this type of analysis was used in the studies in which cycling was found. The interpolation of missing values was found to introduce apparent cycling, and the results of the analysis of daily neutrophil counts was no different than that obtained with a series of random numbers.

The effect of a single injection of vinblastine sulfate was studied in 50 mongrel dogs. Nine of 34 dogs given 0.2 mg./Kg. of VLB died with gastrointestinal toxicity and the mortality rate increased as the dosage of VLB was increased. The morphologic pattern of leukocyte suppression and recovery in the bone marrow and blood was studied in detail in surviving animals. The cells of the bone marrow were markedly affected by VLB. Within 4 hours there was an increase in the number of cells in metaphase and, by day 1, virtually all proliferating leukocytes and erythrocytes had disappeared. An orderly repopulation of the bone marrow followed. The neutrophils, eosinophils, lymphocytes and monocytes of the blood were all markedly altered in concentration after VLB. Each type of cell first decreased to abnormally small numbers and then increased to abnormally large numbers in the blood. The curve of disappearance from and reappearance in the blood differed for each cell type. The changes in blood neutrophil number and morphology were correlated with changes in the blood neutrophil precursor cells of the marrow. The following conclusions were reached concerning the neutrophils and the assumptions implicit to these conclusions were detailed. 1. In the dog, the marrow contains enough post-mitotic granulocytes to replace those lost from the blood for at least 3 to 4 days. 2. The release of mature neutrophils from the bone marrow is a function of the rate at which blood neutrophils are lost and proceeds normally even when the marrow granulocyte reserve is partially depleted.

Present knowledge concerning the kinetics of granulopoiesis has been reviewed and quantitative data concerning granulokinetics in normal human subjects are presented. A. When granulocytes are labeled in vitro and returned to the circulation of the donor, the distribution of the cells in the circulation and the rate of disappearance of the cells from the circulation can be measured. 1. The total blood granulocyte pool (TBGP) consists of two compartments which are in equilibrium with each other. These pools have been designated the circulating granulocyte pool (CGP) and the marginal granulocyte pool (MGP). The size of the pools has been measured in 109 normal male subjects. The mean values, expressed as numbers of cells x 107 per Kg. of body weight were as follows: TBGP, 70; CGP, 31; and MGP, 39. The mean ratio of the CGP to the TBGP was 0.44. 2. The labeled granulocytes leave the TBGP in an exponential fashion with a mean half-time disappearance (T½) of 6.7 hours as determined in 56 normal male subjects. No evidence has been obtained for a return of granulocytes to the blood. 3. The mean value for the granulocyte turnover rate (GTR) in 56 normal male subjects was 163 x 107 granulocytes per Kg. of body weight per day. Thus, the TBGP turns over 2.3 times per day and the turnover time for the TBGP is 10.4 hours. B. When granulocytes are labeled in vivo by the intravenous administration of DFP32, the rate of disappearance of granulocytes from the circulation and the time required for myelocytes to divide, mature and appear in the blood can be measured. In addition, the generation time of myelocytes can be approximated. From the time parameters and the GTR, the bone marrow pool sizes and turnover times can be calculated. These determinations and calculations have been made for a group of 21 normal male subjects. 1. The mean half-time disappearance (T½) of in vivo labeled granulocytes from the circulation was 7.2 hours. This value agrees well with the value of 6.7 hours obtained after the in vitro labeling of granulocytes. 2. The mean time required for myelocytes to divide, mature and appear in the blood was 11.4 days. 3. The mean generation time of myelocytes was estimated to be not more than 2.9 days. 4. The total granulocyte pool in the bone marrow (neutrophilic myelocytes, neutrophilic metamyelocytes and PMN neutrophils) was calculated to be 186 x 108 cells per Kg. of body weight with a mean turnover time of 11.4 days. The myelocyte pool was estimated to be 41 x 108 cells per Kg. with a turnover time of 2.5 days; the metamyelocyte pool consisted of about 76 x 108 cells per Kg. with a turnover time of 4.7 days; the average size of the mature marrow PMN neutrophil pool was 69 x 108 cells per Kg. of body weight with a turnover time of 4.2 days. C. A kinetic model for granulopoiesis, based on the studies with the DFP32 label, is presented. In this model, myelocytes are depicted as approaching a self-perpetuating population of cells. Some cells enter this population from populations which are less mature but this latter source of cells is small under conditions of normal steady state kinetics. One of the daughter cells of a myelocyte division remains in the myelocyte population to divide again. The other daughter cell enters the metamyelocyte population. The metamyelocyte and PMN neutrophil population is incapable of division and cells move through this population in sequential fashion in the process of maturation. The cells then enter the blood where they equilibrate rapidly between the two blood compartments. The cells are removed from the total granulocyte pool in a random fashion. There is no appreciable pool of granulocytes in the extramedullary tissues of normal subjects and granulocytes do not return from the tissues to the blood. The entire movement of granulocytes from marrow to tissues is uni-directional.

1. A method has been presented by which granulocytes can be labeled in vivo with diisopropylfluorophosphate containing radioactive phosphorus. The leukocytes are isolated from blood by dextran sedimentation of erythrocytes and are then treated with gramicidin and lysolecithin to remove remaining red cells. Platelets are removed by differential centrifugation. The isolated leukocytes are placed between two squares of scintillating plastic and counted with a scintillation counter. 2. Leukocytes essentially free of erythrocytes and platelets can be obtained by the method outlined. The efficiency of the plastic scintillation counting method for radioactive phosphorus is about 74 per cent and leukocyte samples obtained from 20 ml. samples of normal blood can be counted with a reproducibility of ±10 per cent. 3. The administration of 2 mg. of diisopropylfluorophosphate either intramuscularly or intravenously is without significant toxic side effects. 4. No evidence has been obtained that the label damages the leukocytes. 5. No evidence has been obtained that the label elutes from leukocytes under the conditions of these studies. 6. Diisopropylfluorophosphate labels granulocytes for a brief period of time following injection. The label is not reutilized after death of the cells.

SummaryThe mechanism by which bacterial endotoxin induces granulocytosis in man has been investigated by labeling granulocytes with radioactive diisopropylfluorophosphate.In man, a moderate dose of bacterial endotoxin produces a granulocytosis. By labeling circulating granulocytes with DF32P and later giving endotoxin intravenously, the rates of granulocyte inflow and egress from the blood were measured. Equations were written which express these flow rates as a function of the variables derived from the experimental data. These equations were solved for several time intervals during the 24-hr experiments in each of 12 normal subjects. In the six subjects in whom there was a significant granulocytic response to endotoxin there was a mean increase of 180% (58-383) in the rate of granulocyte inflow to the blood and 150% (24-420) in the rate of egress of granulocytes from the blood during the 5-hour period immediately after endotoxin injection.The remaining six subjects did not have a granulocyte response be...

These studies were designed to determine whether colony stimulating factor (CSF) and diffusible granulocytopoietic stimulator (DGS) represented a single substance which stimulates the production of granulocytes in vitro and in vivo. The effect of endogenous CSF upon DGS activity was studied after injection of 40 µg endotoxin. This resuited in both DGS activity and high serum CSF levels, but the time of appearance and duration of the two activities followed different patterns. In particular, CSF peaked and was declining 24 hr following endotoxin at which time DGS was not yet detectable. Then, as serum CSF fell, the DGS activity rose. These data support the concept that the DGS activity detectable with short term Millipore chamber cultures is not due to CSF and suggests the effects of CSF in vitro and DGS in vivo are due to different factors.

In these studies, the DF32P leukokinetic technique has been modified so that neutrophil kinetics may be studied in the nonsteady state. In order to achieve this modification, an acid citrate solution was used in preparing leukocytes for radioactive assay. This results in a suspension free of cell agglutination so that a specific activity related only to neutrophils is obtained. This technique has been successfully employed in the study of the early phase of cortisol-induced granulocytosis, allowing measurement of cell flow rate in and out of the circulating granulocyte pool. This method is also useful in the study of subjects with pronounced neutropenia.

Dog granulocytes were labeled in vitro with radioactive diisopropylfluorophosphate (DFP32) and then returned to the circulation of the donor. Granulocytes were separated from whole blood by utilizing hexadimethrine bromide as the sedimenting agent and saponin as a lysing agent. The labeled granulocytes disappeared from the circulation in an exponential fashion with a mean (±1 sd) half-time disappearance of 5.6 ± 0.95 hr. The size of the total blood granulocyte ( TBGP), circulating granulocyte ( CGP), and marginal granulocyte ( MGP) pools, and the granulocyte turnover rate ( GTR) were measured in 31 normal, unanesthetized dogs. The mean values ± 1 sd, expressed as number of cells x107/kg body wt., were as follows: TBGP, 102 ± 34.8; CGP, 54 ± 20.7; MGP, 48 ± 23.4; and GTR, 305 ± 111.5 cells/kg day. The values observed in anesthetized and in unanesthetized, splenectomized dogs were not significantly different from the above values.

The mechanism by which adrenocortical steroids induce granulocytosis in man has been investigated using granulocytes labeled with radioactive diisopropylfluorophosphate. After an intravenous injection of 200 mg of cortisol was given to five normal subjects, the mean value for the total blood granulocyte pool increased from 79 to 138 x 10(7) cells per kg of body weight and reflected an increase in the size of both the circulating granulocyte pool and the marginal granulocyte pool. When granulocytes in the circulation were labeled with diisopropylfluorophosphate and granulocytosis was induced later by the intravenous administration of cortisol, the rate of decline of granulocyte specific activity was increased, indicating that the blood pool was being diluted at an accelerated rate by unlabeled cells entering from the bone marrow. The rate of egress of granulocytes from the blood pool to an inflammatory exudate was studied by the "skin window" technique. After the administration of cortisol, there was a mean reduction in the cellularity of induced inflammatory exudates of 75%. However, this reduction in cellularity varied considerably from subject to subject (45-98%). From these studies we can infer that steroids induce an absolute granulocytosis by decreasing the rate of egress of cells from the total blood granulocyte pool as well as by increasing the influx of cells from the bone marrow. By model simulation studies of the non-steady state induced by cortisol injection, it has been possible to quantitate these rate changes. In the present studies cortisol injection resulted in a mean decrease in blood granulocyte egress of 74% (1-99%) and a mean increase in cell inflow of 450% (300-750%).

In the course of evaluating the fine-needle aspiration technic a toxoplasma cyst was identified in a lymph node excised from a patient in whom toxoplasmosis subsequently was confirmed serologically. This is the first reported case in which a cyst was identified by this method. The recognition of a cyst and characteristic cytologic features in the aspirate demonstrates the utility of fine-needle cytologic examination in diagnosing toxoplasmic lymphadenitis.

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.

Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.

The Southwest Oncology Group evaluated 51 patients with a histologic diagnosis of metastatic adenocarcinoma and an occult primary tumor. Even though all patients received an extensive diagnostic evaluation, only six (12%) primary sites were found. Thirty-six patients whose primary tumor sites remained occult were randomized to receive either 5-FU or combination chemotherapy (5-FU, doxorubicin, and cyclophosphamide [FAC]). There were no responses in either group. The median survival with 5-FU was 105 days and with FAC was 95 days. Toxicity with FAC was more common and more severe.

One-hundred-fourteen evaluable patients with metastatic soft tissue or bony sarcoma with measurable disease were treated with Adriamycin (doxorubicin) administered intravenously at a dose of 60 mg/M2 on day 1, followed by DTIC (dacarbazine) at a dose of 750 mg/M2; courses were administered at 3-week intervals. Ten complete remissions and 17 partial remissions were observed. The most responsive cell type was malignant fibrous histiocytoma with a response rate of 54%. This treatment schedule was very well tolerated, with only moderate myelosuppression and moderate nausea and vomiting. Cardiac toxicity was identified in three patients, with two patients demonstrating electrocardiogram (EKG) changes and arrhythmias and only one patient developing heart failure. The 24% overall response rate suggests no compromise in activity on this schedule, with a significant reduction in toxicity.

Aclarubicin, a new anthracycline antibiotic, was used to treat 24 adult patients with refractory adult leukemia, using a total dose of 300 mg/m2 (75 mg/m2/day X 4). There were 20 patients with acute myelogenous and four with acute lymphoblastic leukemia. Approximately two-thirds of the patients had a Karnofsky score of less than or equal to 2, and two-thirds had received two or more previous induction programs. Interim bone marrow evaluation was obtained in 18 of 30 remission induction courses and revealed marked hypocellularity in 14, inadequate specimens in three, and persistent disease in one. Seven patients received more than one course. Two patients refused further therapy. In patients with myelogenous leukemia, there were two complete remissions lasting 10 and 16 months and one partial remission lasting 4 1/2 months. There were no responders in patients with lymphoblastic leukemia. Toxicity included profound leukopenia and thrombocytopenia, moderate nausea and vomiting, diarrhea, and mucositis. There were no cardiac symptoms associated with the drug infusion, but there were three late events possibly associated with anthracycline cardiotoxicity. Used in this dosage schedule, aclarubicin is an active, but toxic, agent in the acute myelogenous leukemias.

Since lithium causes granulocytosis in some patients, its effect upon granulocyte production was investigated using mouse marrow in the agar culture system. When lithium was added to semisolid cultures of mouse marrow, there was no stimulation of colony formation in the absence of colony-stimulating activity (CSA). In addition, lithium did not potentiate the action of already formed CSA. However, lithium did stimulate the production of CSA by lung tissue. Lithium enhancement of CSA production was blocked by puromycin, indicating that lithium action required active new protein synthesis. It was concluded that lithium promoted enhanced granulocyte production in vitro by stimulating the synthesis of CSA.

The kinetics of blood neutrophils was investigated by means of the in vitro radioactive diisopropyl fluorophosphate method in 35 patients with a chronic, steady-state neutropenia. There were 17 patients in whom the half disappearance time of neutrophils was normal. In 10 of these patients, the production of neutrophils was low and in 7, production was normal. In 18 patients the half disappearance time of neutrophilic granulocytes was shorter than normal. The production of neutrophilic granulocytes was low in five of these patients, normal in eight patients, and increased in five. An attempt was made to correlate other laboratory measurements with the kinetic picture, but no relationship was found; the marrow neutrophil reserve as measured by endotoxin or cortisol injection; marrow cellularity on aspiration or biopsy; in vitro-labeling index with (3)HTdR; or serum lysozyme concentration proved of no value in identifying the various kinetic groups. The only finding that seemed to correlate with the kinetic picture was the presence or absence of splenomegaly. In 12 of the 18 patients with a short half disappearance time, splenomegaly was present whereas in 15 of 17 patients with a normal half disappearance time, there was no splenomegaly. Of 20 patients with greater than 1000 neutrophils per mm(3), 17 were found to have a normal total-blood neutrophil pool. Thus these patients, with many of their cells marginated, agree to have a "shift neutropenia."Myelocyte to blood transit time and myelocyte generation time, as measured in seven patients by in vivo labeling with diisopropy fluorophosphate, proved to be essentially normal. Thus, it appears that in chronic neutropenia, increased or decreased production of neutrophils is accomplished by increasing or decreasing early precursor input into the system.

Ferrokinetic studies were performed in three copper-deficient swine and the results have been compared with similar studies in 18 normal pigs. The mean value for the plasma iron turnover rate in the deficient swine was 1.76 mg./kg. day; for the red cell iron incorporation rate, 1.24 mg./kg. day; for the red cell iron turnover rate, 1.18 mg./kg. day; for the red cell life span, 13 days. Corresponding figures in the normal swine were 1.11 mg./kg. day, 1.01 mg./kg. day, 0.59 mg./kg. day and 63 days, respectively. The red cell life span was measured by the use of radioactive chromium in a total of 26 pigs. The mean erythrocyte half-life of normal cells transfused into normal pigs was 17 days. The mean half-life of erythrocytes from copperdeficient swine transfused into copper-deficient swine was 9 days. The mean half-life of red cells from control animals transfused into copper-deficient swine was 16 days while that of erythrocytes from copper-deficient swine transfused into normal pigs, was 13 days. The mean half-life of cells from iron-deficient pigs transfused into iron-deficient pigs was 19 days. It is concluded that copper deficiency anemia results from both a shortened erythrocyte survival time and limited capacity of the bone marrow to produce red cells. It is suggested that copper is an essential component of erythrocytes in swine.

ConclusionsUptake of tritiated diisopropylfluorophosphate (H3-DFP) by various morphologic types of leukocytes after labeling in vitro and in vivo has been studied. When leukocytes from normal subjects and patients with leukemia were labeled in vitro, myelocytes labeled most intensely. Metamyelocytes and polymorphonuclear (PMN) neutrophils contained about half as many grains/cell as the myelocytes. Lymphocytes, eosinophils, and basophils did not bind significant amounts of DFP under the conditions of this study while a few monocytes were lightly labeled. Granulocytes in both blood and bone marrow were labeled after intravenous injection of H3-DFP. Relative degree of labeling was as follows: blood PMN neutrophils, 1.0; marrow PMN neutrophils, 0.3; marrow metamyelocytes. 0.2: and marrow myelocytes, 0.6. None of the other formed elements in either blood or bone marrow contained significant amounts of the label.