To report five cases of acute monocytic or myelomonocytic leukemia after chemotherapy with 4-epidoxorubicin for breast cancer and to evaluate the risk of leukemia after the use of this drug.

Female breast cancer is a major medical problem with significant public health ramifications. During the next decade, more than 1.5 million women in the United States will be newly diagnosed with invasive breast cancer. The Breast Cancer Prevention Trial (BCPT) is an NIH-sponsored study which will determine whether long-term tamoxifen therapy is effective in: 1) Preventing invasive breast cancer, 2) Lowering the incidence of fatal and nonfatal myocardial infarction, and 3) Reducing the incidence of bone fractures. Sixteen thousand women, including at least 100 from West Virginia who are > or = 35 years of age at increased risk for breast cancer, will be randomized between placebo and tamoxifen during a two-year period. For each participant, the annual and lifetime probability of developing breast cancer will be estimated utilizing a computerized model of risk assessment. The placebo or tamoxifen will be administered for at least five years. Toxicity, compliance, monitoring of quality-of-life assessment, and lipid and lipoprotein evaluations are major components of this trial.

To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer.

Individuals with a family history of colorectal cancer are believed to be at an increased risk of developing colorectal neoplasia. To estimate this risk and the potential yield of screening colonoscopy in this population, we recruited and prospectively colonoscoped 181 asymptomatic first-degree relatives (FDR) of colorectal cancer patients and 83 asymptomatic controls (without a family history of colorectal cancer). The mean ages for the FDR and control groups were 48.2 +/- 12.5 and 54.8 +/- 11.0, respectively. Adenomatous polyps were detected in 14.4 percent of FDRs and 8.4 percent of controls. Although 92 percent of our FDRs had only one FDR afflicted with colon cancer, those subjects with two or more afflicted FDRs had an even higher risk of developing colonic adenomas (23.8 percent) than those with only one afflicted FDR (13.1 percent). A greater proportion of adenomas was found to be beyond the reach of flexible sigmoidoscopy in the FDR group than in the controls (48 percent vs. 25 percent, respectively). Logistic regression analysis revealed that age, male sex, and FDR status were independent risk factors for the presence of colonic adenomatous polyps (RR = 2.32, 2.86, and 3.49, respectively; P less than 0.001). Those at greatest risk for harboring an asymptomatic colonic adenoma are male FDRs over the age of 50 (40 percent vs. 20 percent for age-matched male controls). Based on probability curves, males with one FDR afflicted with colon cancer appear to have an increased risk of developing a colonic adenoma beginning at 40 years of age. Our results document, for the first time, an increased prevalence of colonoscopically detectable adenomas in asymptomatic first-degree relatives of colon cancer patients, as compared with asymptomatic controls, and support the use of colonoscopy as a routine screening tool in this high-risk group.

We evaluated minimal residual disease (MRD) in 23 CD5 + B-chronic lymphocytic leukemia (CLL) patients who achieved clinico-hematological remission confirmed by bone-marrow biopsy. MRD was evaluated by dual marker analysis flow-cytometry using CD5 and CD19 markers, and by the study of Ig heavy chain gene rearrangements using the fast polymerase chain reaction (PCR). According to our laboratory conditions patients were considered to be in complete phenotypic remission when total CD19+ cells were < 25% and the ratio of CD5 + CD19 + /CD19 + cells was < 25%. According to these strict criteria only 9 of the 23 patients were in complete phenotypic remission. In order to evaluate the sensitivity of the above method, PCR analysis of the configuration of the Ig heavy chain gene region was performed in 12 of these patients. Five of 7 patients in complete phenotypic remission retained a detectable monoclonal rearrangement of the Ig heavy chain gene. For the remaining 5 patients in partial phenotypic remission, only one failed to show a monoclonal band and this is probably explained by the presence of an unusual gene rearrangement. In conclusion, this study suggests that PCR is more sensitive than dual marker flow-cytometry for evaluation of residual disease and that it is indeed possible to achieve complete remission at the molecular level, in B-CLL. Nevertheless, we suggest a word of caution as this was a retrospective study, and samples were not assessed before treatment. Thus the possibility that apparent molecular remission might correspond to unusual gene rearrangements cannot be completely excluded in these cases.

Standard or conventional treatment of chronic myeloid leukemia (CML) had little effect on the course and the duration of the disease. Treatment with human natural and recombinant alpha-interferon (IFN) was shown to induce hematologic responses, together with partial or complete repopulation of the marrow with Ph negative cells (karyotypic response). These findings prompted a prospective comparison of IFN and conventional treatment in CML.

In vitro data suggest a synergistic antiproliferative effect of different cytokines. In four clinical studies chronic myelogenous leukemia (CML) patients were treated with interferon (IFN)-alpha alone or IFN-alpha combined with either low-dose IFN-gamma or tumor necrosis factor (TNF)-alpha. The best response was achieved in previously untreated patients with good prognostic factors and highest tolerable IFN dose for maintenance treatment. Breakpoint localization within the major breakpoint cluster region did not correlate with response to IFN. In a randomized study of IFN-alpha versus IFN-alpha combined with IFN-gamma, no differences in response rates were observed. Patients with primary or secondary resistance to these treatment modalities received a combination therapy with IFN-alpha and TNF-alpha. In these patients, a decrease in leukocyte counts was noted, but no cytogenetic improvement occurred.

Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease.

Treatment decisions must be made on 9000 axillary node-negative breast cancer patients each month in the United States. Which of these patients will benefit from adjuvant therapy is a major question. Valid methods are needed to distinguish those patients who are "cured" from those who will suffer a cancer recurrence. A complex network of prognostic variables enters into the treatment decision, together with a risk-versus-benefit assessment. We are using a neural-network-based form of artificial intelligence that, once "trained" with data representing an event and its outcome, can identify subsets of patients with low recurrence risks. Larger data sets are being evaluated with the hope of introducing the neural-network technique to routine clinical practice.

An ancillary study (INT 0076) to the Intergroup clinical trial of node-negative breast cancer patients (INT 0011) was performed to retrospectively evaluate DNA flow cytometry measurements of ploidy (DNA content) and proliferative capacity (S-phase fraction) for their ability to predict time to recurrence. Of the 915 patients eligible for the clinical trial, 788 were registered for the ancillary flow cytometry study (INT 0076). Four hundred and three of these patients [estrogen receptor (ER)-positive, tumor size less than 3 cm] had been registered to the observation arm of the clinical trial and 385 (ER-negative and/or tumor size greater than or equal to 3 cm) had been randomly assigned to adjuvant chemotherapy (cyclophosphamide, methotrexate, fluorouracil, and prednisone for six cycles) or to observation. Paraffin blocks from 95% (748 of 788) of these patients were obtained, 712 of which had sufficient cancer tissue to be evaluable for the flow cytometric assay. DNA ploidy status (DNA diploid vs DNA aneuploid) was evaluable for 565 (79%) specimens, 64% of which were aneuploid. Proliferative capacity was estimated by the percentage of cells having an S-phase DNA content, using a trapezoidal modeling algorithm(s) as previously described. The median S-phase value for the entire group (both registered and randomly assigned patients) was 6.97%, which defined the cutoff for interpretation of high or low S-phase values. With a median follow-up time of 4.55 years, S-phase fraction, but not ploidy status, is a significant predictor for time to recurrence in both the randomly assigned and the untreated population (observed registered group and observed randomly assigned group).(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated breast cancer specimens from 241 patients of a controlled clinical trial by means of DNA flow cytometry. We report the correlations between DNA index (DNI) and fraction of cells in S-phase (SPF) and other prognostic parameters. Both univariately and in a Cox model, the predictive power of these factors is evaluated after a follow-up of more than 10 years. There are strong correlations between DNI and SPF (P = 0.0001) and between flow cytometry parameters and clinical and histopathological factors such as axillary lymph node involvement, tumour size and histological grade. In univariate analysis DNI fails to provide prognostic information, whereas SPF turns out to be able to differentiate between patients at high and low risk for relapse and death (P = 0.002). In the multivariate Cox model, too, SPF is an important prognostic parameter with respect to patient survival (relative risk: +86%), only surpassed by nodal involvement. DNI, however, turns out to be an independent predictor of relapse free survival and distant recurrence free survival. By combination of DNI and SPF, patients can be divided into three prognostic subgroups. We conclude that data from DNA flow cytometry can be of great importance for the decision on the level of aggressiveness of adjuvant therapy for an individual patient and therefore may help to avoid overtreatment and toxicity.

Specimens from 24 chemically induced canine non-small cell lung cancers (NSCLC) were xenotransplanted into nude mice. Twenty-one tumour lines were established in serial transplantation; four were from NSCLC that arose from orthotopically induced NSCLC in four dogs, and 17 were from NSCLC that arose heterotopically in 15 subcutaneous bronchial autografts (SBA) in seven dogs. Distant metastases developed in recipients of two orthotopic NSCLC after three and eight consecutive tumour growth cycles; no metastases have occurred after three and six growth cycles of two other orthotopic tumour lines. Recipients of eight heterotopic tumour lines developed metastases after 3-9 consecutive tumour growth cycles, while no metastases have occurred after 4-11 growth cycles in recipients of nine other heterotopic tumour lines. In three instances, both metastasizing and non-metastasizing tumour lines resulted from NSCLC that arose in different SBAs in the same dog. These findings indicate that, in the canine SBA bronchogenic cancer model as expanded by tumour xenotransplantation, those molecular events involved in both the initiation and the full progression of a single cancer may be investigated serially and concomitantly.

The DNA content was analyzed in paraffin-embedded material from 167 patients with node-positive breast cancer to learn whether specimen sonication and multiparameter ploidy analysis (MPPA) (using DNA content and light scatter) could improve the strength of ploidy as a prognostic variable. Sonicated specimens were found to have fewer aggregates, a lower percentage of cells in S-phase (%S) and G2M phase than the corresponding nonsonicated specimens. The results using MPPA predicted the prognosis better because they allowed detection of small aneuploid peaks in histograms classified as diploid or tetraploid using DNA content alone. Ploidy was a significant univariate factor, and patients with tetraploid tumors had the best survival. In the multivariate analysis, if other routine factors were examined preferentially, ploidy and %S did not provide additional prognostic information for survival. This study of paraffin-embedded breast cancers suggested that sonication and MPPA may improve the ploidy analysis in certain cases and that tetraploidy may be a favorable ploidy pattern in this group.

To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.

We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.

This is a presentation of some preliminary data from SPCG-I, a multicenter study started in 1984 by the Scandinavian Prostatic Cancer Group. It is a randomized double-blind study comparing estramustine phosphate and diethylstilbestrol in the primary treatment of 195 patients with T1-4, NX, M1, G2-3 prostatic cancer. The code is not yet broken. This presentation describes the impact of the pretreatment parameters performance status, pain, tumor burden, grade and DNA-ploidy of the prostate tumor, on time to progression and overall survival. DNA studies have so far only been completed in 66 of the 195 patients. For the whole group of 195 patients, pain (p less than 0.004) and tumor grade (p less than 0.02) had the most significant impact on time to progression, and performance status (p less than 0.01) and grade (p less than 0.03) on overall survival. In the small group of 66 patients where the DNA pattern of the primary tumor was evaluated, no parameter had any significant correlation to time to progression and overall survival. This study is still continuing.

In order to compare the effects of interferon versus hydroxyurea for the treatment of chronic myelogenous leukaemia (CML), 58 CML patients, having received no previous treatment, were randomized into two treatment groups (hydroxyurea or interferon) for an open multicentre study from 1 May 1987 until 1 July 1990. Fifty patients were evaluable: 24 in the interferon group and 26 in the hydroxyurea group. Haematological response was obtained in 16/24 interferon-treated patients and 23/26 hydroxyurea patients. Failure to obtain haematological remissions occurred in eight of 24 interferon-treated patients and in three of 26 hydroxyurea patients. Four interferon-treated patient failures and one hydroxyurea-treated failure were due to drug intolerance. Progression occurred in one interferon-treated patient and in three patients given hydroxyurea. Fourteen of 16 patients in the interferon group and 17/23 in the hydroxyurea group continue on study and show no progression.

Sixty patients with Ta and T1 bladder cancer were randomized between treatment with resection only and resection and instillations with either Adriamycin or Mitomycin C. Treatment lasted for one year and patients were evaluated after a mean follow-up of 35 to 47 months if progression had not occurred. Mitomycin C was superior in reducing the recurrence rate. Progressive disease was observed in 17 patients regardless of therapy but in all patients DNA aneuploidy could be identified at a risk factor.