Low-dose continuous infusion 5-fluorouracil. Evaluation in advanced breast carcinoma.

Low-dose continuous infusion 5-fluorouracil (LDCI-FU) was administered to 28 women with advanced breast carcinoma. Daily doses ranged from 175 to 250 mg/m2. The LDCI-FU was delivered continuously until the appearance of toxicity and was reinstituted at a 20% dose reduction after toxicity completely resolved. Patients with a median age of 56 years and a median performance status of 60% (Karnofsky) had been previously treated with combination chemotherapy. Complete responses were observed in two patients with soft tissue metastases. Thirteen patients experienced partial responses with a median duration of response of 4+ months. Partial responses were predominantly observed in soft tissue disease; however, five patients with visceral metastases experienced partial tumor regression. Median survival for the study group was 4+ months. Hormonal receptor status did not predict response to LDCI-FU. Toxicities included stomatitis, ten patients; hand-foot syndrome, eight patients; mild leukopenia, two patients; moderate thrombocytopenia, two patients; diarrhea, three patients; ataxia, three patients. Catheter-related toxicities of sepsis and/or thrombosis occurred in six patients. Because of the demonstrated activity in previously treated patients (53% response rate), LDCI-FU should be investigated in combination chemotherapy regimens in untreated breast cancer patients.

Treatment of metastatic breast cancer with AZQ: a phase II trial.

Seventeen patients with metastatic breast cancer who had failed prior chemotherapy were treated with intravenous AZQ at a dose of 15-20 mg/m2 weekly for four consecutive weeks followed by a two-week rest period. No responses were observed. Myelosuppression was the dose-limiting toxicity. One patient experienced massive liver infarction possibly related to AZQ. Our data suggest that this agent at the schedule and dosage used is of no benefit in pretreated breast cancer patients.

Legionella feeleii-associated pneumonia in humans.

Legionella feeleii has been implicated by serologic studies as the causative agent in an outbreak of Pontiac fever and has been recovered from an institutional water source. Pneumonia caused by this agent has not been described previously. The authors have isolated L. feeleii from two immunosuppressed patients with community-acquired pneumonia and from an institutional water source. One patient survived after treatment with erythromycin. The other patient was leukopenic and died of pneumonia. Isolates exhibited typical cultural and biochemical features of L. feeleii and reacted with L. feeleii serogroup 1 antiserum. L. feeleii serogroup 1 is now known to cause not only Pontiac fever but also pneumonia in humans.

A phase II study of cis-diamminedichloroplatinum II for advanced breast cancer. Two dose schedules.

Thirty-six (36) women with metastatic breast cancer refractory to conventional therapies were treated with cis-diamminedichloroplatinum II. Two dose schedules were used sequentially. The first 15 patients received platinum at a dose of 15 mg/m2 daily for 5 days at 28-day intervals. No response was noted in this group. Subsequently, 21 patients were treated with a dose of 100-120 mg/m2 at 28-day intervals, but with additional induced diuresis with saline, furosemide, and mannitol. Among 13 patients evaluable for response, 2 partial responses were observed.

The practicality of chronic hepatic artery infusion therapy of primary and metastatic hepatic malignancies: ten-year results of 124 patients in a prospective protocol.

Ten-year results are presented of 124 patients with malignancy apparently limited to the distribution of the hepatic artery, treated to prospective protocol with continuous infusion of 5-FUdR through an hepatic artery catheter. Nearly all patients had moderate to massive hepatic replacement. Of 88 patients with colorectal carcinoma, 64 (73%) had clinically objective and subjective remission. Median survival for responders was 13 months; for the entire group, ten months. Of 13 patients with hepatoma, nine had clinically significant regression with a median survival of 11 months. Ten patients had carcinoma of the gall bladder or bile duct with seven obtaining clinically significant regression. Complications encountered are discussed and are similar to other series. Of the patients experiencing clinically significant remission, all but one reached the complete independence performance status, and 84% reached normal activity levels. Thus, for hepatic localized tumor, this therapy is worthwhile and practical.

Estrogen receptors and responsiveness of advanced breast cancer to chemotherapy.

We reviewed 89 patients with disseminated breast cancer who had at least one valid estrogen receptor (ER) assay and who underwent one or several trials of chemotherapy. The responses were assessed by two independent extramural reviewers. Of the 89 patients, 81 were evaluable; 28 of 36 (77.8) ER-positive (ER+) and 28 of 45 (60.7%) ER-negative (ER-) tumors reached at least one remission. Of patients who had received Adriamycin-containing therapy, 13/20 (65%) ER+ and 12/34 (35.3%) ER-tumors experienced a remission . ER+ breast cancer tends to respond better to Adriamycin-containing combinations than ER-negative tumors. This study does not support the thesis that lack of estrogen receptor in breast cancer predicts favorable for response to chemotherapy.

Relation of tumor content of estrogen and progesterone receptors with response of patient to endocrine therapy.

The levels of estrogen (E2R) and progesterone (PgR) receptors in 165 breast tumor biopsies have been determined. Seventy-seven percent of the specimens contained significant levels of E2R; 38.2% were positive for both receptors. Only four tumors displayed the unusual E2R=/PgR+ pattern. Tumors from pre- and postmenopausal patients had similar receptor characteristics. Two-thirds of the six patients with E2R+PgR+ tumors responded to hormonal therapy, whereas only 28.7% of the E2R+/PgR- tumors regressed after similar treatment. These data from a limited number of patients indicate that the presence of E2R and PgR in breast tumor biopsies is of higher prognostic value for response of the patient than in the presence of E2R alone.

Clinical application of estrogen receptor in breast cancer.

Patients with ER positive primary tumors usually have initial metastases at the more favorable sites. Twelve out of 14 patients with ER positive had first site of metastases in either bone or soft tissue. In contrast, 13 of 17 patients with negative ER developed first metastases in viscera. ER positive patients respond better to endocrine therapy and survived twice as long as negative ER patients from the onset of recurrent cancer until death. ER content is not a sufficient criterion for the prediction of the response to endocrine manipulation but serves as useful supplementary information to clinical judgement in to selection of systemic therapy. Prior employment of radiation therapy or the administration of hormones or antihormones, as well as inadequate tumor cells in the specimen and poor procurement of the tumor, can produce spuriously low ER. A protocol to study simultaneous endocrine and chemotherapy in comparison to the sequential approach of endocrine treatment followed by chemotherapy in ER positive patients is desirable.

Clinical correlations of steroid receptors and male breast cancer.

Estrogen receptors (ER) were present in tumor specimens from 29 of 34 cases of male breast cancer. There was a significant negative correlation of ER concentration with age. The quantity of ER tended to correlate directly with progesterone receptor levels, disease-free interval, and response duration among responders, but not to a statistically significant extent. In 13 patients for whom response data were available, no significant correlation was observed between ER levels and either frequency or duration of orchiectomy response. Among the six patients with tumor ER levels of less than 30 fmol per mg of protein, however, only two brief responses to orchiectomy occurred that were of little clinical benefit, while three of seven patients with higher ER responded more favorably. Thus, although this suggests that a relationship between low ER and unfavorable orchiectomy response may emerge as more patients are studied, currently available data do not justify basing therapeutic intervention on ER status of a biopsy in a manner analogous to that used for female breast cancer. Nine of 14 male breast cancer patients had positive progesterone receptor assays and several had androgen or glucocorticoid receptors. Tissue from only three of ten men with gynecomastia had measurable ER, and these were limited to the 4S component on sucrose gradients.

Ureteral obstruction secondary to metastatic breast carcinoma.

An uncommon manifestation of breast cancer is ureteral obstruction secondary to metastatic disease. Five patients who recently developed this complication from two to 20 years after the diagnosis of breast cancer are described. Only two of the five patients had urinary symptoms. All of the patients were older, postmenopausal females who had bone metastases and all had responded to previous hormonal manipulation. Bone scanning was useful in detecting unsuspected hydronephrosis in two patients. Retroperitoneal disease appears to be a complication of long standing breast cancer which is usually hormonally dependent. Routine examination of the bone scan for renal asymmetry may aid in the diagnosis, especially in asymptomatic patients.

Blindness as initial manifestation of meningeal carcinomatosis in breast cancer.

The sudden onset of blindness in adults, with or without a history of malignancy should raise the possibility of meningeal carcinomatosis. The diagnosis is best confirmed with examination of the spinal fluid. The actual mechanism by which blindness occurs is probably a combination of tumor cuffing around the optic nerve, direct infiltration and chronic papilledema. We are reporting two patients with disseminated breast cancer who presented with blindness as the first manifestation of meningeal involvement. Treatment with whole brain radiation and intrathecal Cytosine Arabinoside produced temporary remissions, but both died a few months later of their cancer.

Clinical trial of nafoxidine in adrenalectomized patients with advanced breast cancer.

Antiestrogen compounds are relatively new in the treatment of breast cancer. A clinical trial of Nafoxidine therapy is being pursued in our institution. In a selected group of patients with metastatic breast cancer who had, in the past, undergone adrenalectomy, Nafoxidine therapy produced objective tumor regression in six out of ten patients. Of the six patients whose tumors contained demonstrable estrogen receptors, four showed regression (67%), one patient had stable disease, and one showed tumor progression. Of the four patients in whom estrogen receptor estimation was not done, two had, in the past, shown regression after endocrine therapy and they also showed regression of tumor with Nafoxidine therapy. In patients with metastatic breast carcinoma, who have undergone adrenalectomy in the past, a therapeutic trial with Nafoxidine may be worthwhile particularly in patients who have demonstrable estrogen receptor in the tumor of those who have in the past shown regression of tumor after endocrine therapy.

In vitro responses of focal hyperplastic tissue of the human adrenal zona fasciculata to ACTH.

The temporal cAMP, cortisol and aldosterone responses to ACTH of focal hyperplasia of the zona fasciculata and of normal human adrenocortical tissue were investigated. ACTH significantly increased cAMP levels (1 min) and cortisol output (2 min) in normal adrenal tissue but not in hyperplastic tissue. However, following ACTH treatment cortisol and aldosterone production were depressed in the abnormal adrenal tissue below the untreated or the ACTH stimulated normal adrenal tissue. In addition, basal cortisol and aldosterone production of the hyperplastic adrenal tissue was elevated above that of the normal adrenal tissue. These findings suggest that the cAMP second messenger concept may be only one of several mechanisms in the modulation of human adrenocortical function.

Mitochondrial redox components of human adrenocortical steroid hydroxylases under physiological conditions and in focal hyperplasia of the zone fasciculata.

Cytochrome P450, aa3 and adrenodoxin were characterized in human adrenocortical mitochondria. Human adrenodoxin demonstrated a distinctive electron paramagnetic spectrum exhibiting anisotropic g values indicative of axial symmetry. The observed g values were (formula: see text). Adrenodoxin content of crude human adrenal mitochondria was 0.65 +/- 0.01 nmol/mg of mitochondrial protein and was in a stoichiometric 1:1 molar ration with cytochrome P450. Mitochondrial cytochrome P450 (0.62 nmol/mg mitochondrial protein) and aa3 (0.19 nmol/mg mitochondrial protein) levels were determined in a normal human adrenal A patient receiving ACTH (3d) demonstrated a doubling of P450 content, while cytochrome aa3 levels remained unchanged. ACTH plus hydrocortisone therapy (3d) increased both P450 and aa3 levels, however 24 h hydrocortisone therapy alone was without effect. An area of focal hyperplasia of the zona fasciculata also demonstrated P450 and aa3 levels elevated above the contralateral and normal human adrenal levels. The possibility of hormonal control of human adrenal mitochondrial cytochromes P450 and aa3 is suggested.

Eight-day survival without adrenal steroids.

A patient with advanced breast cancer who had undergone a total bilateral adrenalectomy in the past refused adrenal steroid replacement therapy with the idea that this would be the easiest and quickest way to end her life. However, she continued to live for more than eight days. Survival under these circumstances is unusual, and the terminal course of her illness is described.

The surgical implications of estrophile protein estimations in carcinoma of the breast.

Assays of estrophile protein (ER) in 161 patients with no previous additive or ablative hormonal therapy have been analyzed; 47.2 percent were ER positive; 52.8 percent ER negative. A total of 37.5 percent of premenopausal and 50.8 percent of postmenopausal patients had ER-positive tumors. The effects of additive and ablaive hormonal therapy were observed in 75 patients; 63.5 percent of the ER-positive group and 8.6 percent of the ER-negative group responded, but the incidence in the ER-negative group is thought to be spuriously high. The level of the ER content in the ER-positive group did not influence the degree of response. The ER-negative group had a shorter life span after discovery of the tumor and was more likely to develop dominant visceral metastases. Of 15 patients followed with sequential ER assays after hormonal therapy (additive and/or ablative), 14 demonstrated substantial falls in ER levels but these did not correlate with the clinical response. Tumor assayed in nine patients after irradiation of the lesion contained no demonstrable ER. ER assays of breast cancer tissue proved to be a useful but imperfect tool in predicting clinical progress following hormonal maneuvers but some readings may be spuriously low due to imperfect techniques of measurement, prior exogenous hormonal administration or hormonal ablation, and previous irradiation of the tumor.