Faculty Bibliography

Of 398 cases of breast cancer, 350 included data for all of the following: patient age, tumor size, histologic type, presence or absence of lymph node metastasis, nuclear grade of the cancer cells, extent of lymphocytic infiltration around these cells, and estrogen receptor status of the neoplastic tissue. This series is representative of and comparable with those reported in other studies of breast carcinoma. Initial evaluation suggested a relationship of cytologic differentiation and lymphocytic infiltration to estrogen receptor activity. More extensive statistical analyses, however, demonstrated that three factor interrelationships best explain the data concerning nuclear grade, lymphocytic infiltration, and estrogen receptor activity of the tumors in this study. Thus, the results of this investigation serve to warn against inferential judgments based on limited data or restricted evaluation. In addition, the analyses call attention to a significant association between age and lymphocytic infiltration around the tumor cells

To examine the switch from fetal to adult hemoglobin at the cellular level, erythroid progenitor cells from newborn infants and adults were cultured in methyl cellulose with erythropoietin. Individual erythroid colonies were labeled with [3H]leucine at various times, and globin synthesis patterns examined by gel electrophoresis and fluorography. The percent gamma- or beta-globin synthesis was determined from the total of gamma + beta, and the percent G gamma from the total of G gamma + A gamma. The nonparametric correlation coefficients of percent G gamma with percent gamma or beta were obtained. Each group of colonies at each time point was examined separately. In colonies from adult blood, the proportion of G gamma-synthesis did not correlate with the proportion of gamma-synthesis. Colonies from newborn blood fell into two groups. Those that developed from relatively mature progenitor cells, and were seen on day 14, showed a strong negative correlation of G gamma with beta-globin synthesis. However, those newborn colonies that developed from immature progenitors, and were seen later in culture (days 17 and 21), showed no correlation of G gamma with beta-synthesis. These findings are compatible with a clonal model for hemoglobin switching. Fetal progenitors, in which G gamma- and beta-syntheses are negatively correlated, are gradually replaced during ontogeny by adult progenitors. The adult progenitors produce more beta (less gamma), and the proportions of G gamma- and gamma- or beta-synthesis are not correlated

Patients with advanced ovarian carcinoma, Stage III or IV (International Federation of Gynaecology and Obstetrics), were randomized to primary chemotherapy with doxorubicin (Adriamycin) and cisplatin plus or minus hexamethylmelamine, and cyclophosphamide (CHAP). The four-drug CHAP regimen produced a 57% complete clinical response rate and a 26% partial response rate for clinically evaluable patients. The median survival of CHAP patients is 25 months. The two-drug Adriamycin-cisplatin (AP) regimen produced a 43% complete response rate and a 35% partial response rate. The median survival is 18 months. The four-drug regimen produced a significantly longer median survival (28 versus 18 months) for patients with poorly differentiated tumors than for patients with well-differentiated tumors on either treatment. Examination of treatment failure or death by treatment, histology, and size of largest residual tumor and comparison to similar patients treated with AP in this and two preceding controlled trials also suggest that CHAP is superior to AP for patients with poorly differentiated tumors

To explore the hypothesis that low education, associated with high 5-yr sudden-death risk among myocardial infarction survivors demonstrating ventricular arrhythmia, might be a marker for relatively high levels of psychosocial stress, we did telephone interviews with the patients' wives. Analysis of the information obtained on life circumstances and personality attributes resulted in four psychosocial factors that were found to be independent of the patients' educational level. The difference in sudden-death risk in relation to education, given the presence of complex ventricular premature beats in one hour of ECG monitoring, was large and could not be accounted for in multivariate analyses by one or more of these psychosocial factors. Nevertheless, life-table analyses in relation to categorized levels of scores for some of the factors did suggest some modest influences on risk of sudden cardiac death, with severity of disease controlled

HexMF consists of hexamethylmelamine 150 mg/m2 D2-15, mitomycin C (MMC) 10 mg/m2 D2 and 5-fluorouracil (5-FU) 30 mg/kg/day as a continuous infusion D1-5 in 4-5 week cycles. It was designed as an alternative to treating patients with standard single agents in sequence, thereby preventing the testing of new drugs as part of primary therapy. Median survival was 12+ months for patients with measurable and 18+ months for patients with nonmeasurable colorectal cancer. It was 9+ months from the onset of secondary chemotherapy. Toxicity included severe thrombocytopenia (50%), severe leukopenia (25%), and moderate stomatitis (50%). Only one instance of leukopenia was life-threatening. The MMC and 5-FU infusion skeleton provides an attractive strategy for testing new drugs as primary therapy. HexMF itself has a potentially broad antitumor spectrum and excellent acceptance by patients. It is suitable for additional phase II trials

A combination consisting of hexamethylmelamine 150 mg/m2 D2-15, mitomycin C 10 mg/m2 D2 and 5-fluorouracil 30 mg/kg/day as a continuous infusion for 5 days, in 4-5 week cycles, underwent phase II trial as primary therapy for 21 patients with regional and metastatic cancer of the pancreas. Median survival from the onset of therapy was 43 weeks. There were 2 complete responses, 4 minor responses and 6 stable diseases for more than 6 months. Nonambulatory patients were among the responders. There was only 1 life-threatening toxicity (thrombocytopenia) and only 33% of patients had clinically silent severe hematological toxicity. The regimen is well tolerated, active and associated with excellent survival. This regimen is suitable for further confirmatory trials

The ontogenic switch from fetal to adult hemoglobin could be due to gradual replacement of fetal by adult erythroid progenitor cells, each with unique potential hemoglobin expression programs. We have studied globin synthesis in single colonies derived from the BFU-E of human newborn infants and rhesus monkey fetuses, both at the time of the switch. In the 140-day rhesus fetal colonies, beta synthesis ranged from 8% to 44% of (beta + gamma) in 47 colonies. When fetal colonies were arbitrarily defined as those with below 26% beta, and adult colonies those with above 26% beta, we predicted that there would be 12 adult colonies; 14 were observed. The rhesus fetal results were compatible with the presence of two or more classes of progenitors within the population seen at the time of the switch. In the human newborn study, the number of colonies increased fourfold from day 14 to day 21 in culture. beta synthesis also increased. These increases occurred even in cultures from which red, well-hemoglobinized colonies were completely removed as they appeared. New cohorts of late-appearing colonies were derived from immature progenitors. The early colonies showed correlation of G gamma and beta synthesis, but the late colonies did not show this correlation. We had found the latter pattern previously in adult, fetal-like colonies. Thus fetal progenitors in man have high levels of Hb F and G gamma, with correlation of these parameters at the level of single-progenitor-derived colonies; these fetal progenitors are found in fetuses and newborns. Adult, fetal-like progenitors have lower levels of Hb F and G gamma, without any correlation between the levels of each. The adult progenitors appear in newborn infants as the switch occurs, and they are the only class found in adults. Our observations in the simian and human studies support a clonal model for hemoglobin switching.

Fifty febrile severely granulocytopenic patients were given four daily transfusions of 2.2 X 10(10) normal donor granulocytes. Twenty-three (46 percent) responded clinically, although both responders and nonresponders were similar in clinical characteristics at the outset. This study examines the relation between serum opsonic activity before initiation of granulocyte administration and clinical response. Opsonic activity to three test organisms (Escherichia coli 286 and ON 2, and Staphylococcus aureus) and to 15 blood stream isolates from 14 patients was measured as serum-dependent uptake of heat-killed 14C-labeled bacteria by normal donor leukopheresis granulocytes in an in vitro assay and compared with results obtained with a standard normal serum in each assay. At a concentration of 8 percent serum, all patient groups were equivalent to standard (90 to 102 percent) for the three test organisms. When rate-limiting concentrations of serum (1 to 2 percent) were employed, opsonic activity remained similar to standard for S. aureus in all patient groups and for the two E. coli strains in responders (82 to 98 percent). In contrast, opsonins for E. coli decreased to 41 to 50 percent of standard in nonresponders (p less than 0.01). When patients with proved infection were separately analyzed, opsonin activity for E. coli 286 and ON 2 was significantly greater in responders than nonresponders (73.6 versus 34.9 percent and 124.8 versus 58.1 percent, respectively for the two strains) (p less than 0.01). Patients with opsonin activity of 50 percent or greater of standard had a greater response rate (73 versus 19 percent and 45 versus 0 percent for the two E. coli strains) (p less than 0.005 and p = 0.08, respectively). Eight of 10 patients with 75 percent or greater of standard for opsonic activity against their own blood stream isolates also responded, whereas zero of four with opsonins less than 75 percent of standard had a favorable outcome. These results indicate that serum opsonic activity may be a determinant of clinical response to granulocyte transfusion in infected granulocytopenic patients and may be predictive of outcome. We conclude that opsonic activity should be assessed in such patients before granulocyte administration and suggest a trial of plasma infusion in opsonin-deficient patients

Previously untreated patients who had anemia (hemoglobin level, less than or equal to 10 g/dL) caused by myelofibrosis (MF) (16 patients) or other myeloproliferative disorders (13 patients) were given the opportunity to participate in a prospective randomized study-to be treated either with 30 mg/day of oral fluoxymesterone and necessary transfusions or by transfusions alone. Of the 24 patients whose data could be evaluated, four (29%) of 14 responded well to fluoxymesterone therapy (hemoglobin level rise, of greater than 2 to greater than 10 g/dL and relief of symptoms of anemia), whereas, in the transfusion arm, there were no good 'responders'; one of ten patients was a partial 'remitter' (responder), with a rise in the hemoglobin level of 1 to 2 g/dL. All responders to fluoxymesterone therapy showed a 50% or more maximum uptake of injected ferrous citrate Fe 59 into RBC hemoglobin, whereas no nonresponder met this criterion. All responders had MF (marrow more than one third replaced by collagen). There was no significant difference in survival of patients in the two arms of the study