Chemotherapeutic and surgical induction of pathological complete remission and whole abdominal irradiation for consolidation does not enhance the cure of stage III ovarian carcinoma.

Thirty-eight patients with stage III ovarian carcinoma were treated with a protocol consisting of an initial phase of induction of remission with cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD) combination chemotherapy and a second laparotomy for resection of residual tumors, followed by a consolidation phase with curative doses of whole abdominal radiation. Six patients (16%) had stage IIIA disease, ten (26%) IIIB, and 22 (58%) had stage IIIC disease. All patients received three to 14 courses of CHAD chemotherapy with a clinical response rate (complete [CR] and partial [PR]) of 91%. Thirty-three patients underwent the second operation. In 14 patients no residual tumor was found, and in another 11 residual tumors found were totally resected. Thus, 25 of 33 (76%) were classified as in pathological complete remission (PCR) after this operation. Whole abdominal irradiation was well tolerated, although 12 of 29 (42%) of the irradiated patients required more than a 2-week interruption of the treatment course because of leukopenia and/or thrombocytopenia. The actuarial 5-year survival and disease-free survival rates for the whole group were 27% and 17%, respectively, and for the 29 patients who received the complete sequence of the prescribed protocol treatments, 35% and 20%, respectively. A univariate analysis of clinical parameters showed that inherent biological features, such as histology and grade, were the most dominant factors affecting prognosis, and that neither the aggressive surgical approach employed, nor the high-dose whole abdominal irradiation, significantly affected the outcome. The long-term results suggest that although our combined modality protocol was well tolerated, it failed to enhance the cure of stage III ovarian carcinoma. The possible biological and therapeutic vectors affecting this outcome are discussed.

Synthesis and receptor-binding affinity of fluorotamoxifen, a possible estrogen-receptor imaging agent.

Aminotamoxifen was totally synthesized from p-nitrobenzoyl chloride via a Friedel-Crafts acylation. Then, by means of a Balz-Schiemann reaction, aminotamoxifen was converted into fluorotamoxifen. The triazene variation of this conversion, with a 25% yield, enables a rapid, one-step diazotization, incorporating a fluorine atom into the phenyl ring of the tamoxifen. This reaction may be useful for the preparation of low specific activity 18F-labeled tamoxifen, for distribution, and for estrogen-receptor studies. For these in vivo and in vitro studies, fluorotamoxifen was also synthesized from p-fluorobenzoyl chloride, and its chemical intermediates were compared with estradiol and hexestrol, for their receptor binding and competition, as well as for their uterotropic activity. It is demonstrated that tamoxifen and fluorotamoxifen are strong estradiol agonists and partial hexestrol agonists, while aminotamoxifen is a weak estradiol and hexestrol agonist.

In vitro differentiation and establishment of cell lines derived from human myelomonocytic leukemia cells.

Primary cultures of cells derived from 13 patients with acute myelomonocytic leukemia (AMML) were studied with particular emphasis on in vitro proliferation, cell differentiation and the mode for establishment of cell lines. Using irradiated human macrophage monolayers to assist cell growth, we obtained four new cell lines of myelomonocytic origin. All the cell lines were characterized for cytochemical markers and response to phorbol esters (TPA), a differentiation inducing agent. In the absence of any inducing agent, spontaneous differentiation of blast cells into mature macrophages-like cells occurred in 8 out of the 13 primary cultures. Thus, maturation induction by agents such as TPA is not always required in order to obtain leukemic cell differentiation in vitro. The regulation of cell proliferation and differentiation by cellular interactions and by extrinsic soluble products is discussed in detail, in the light of these findings.

Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response.

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.

Platelet-tumor cell interaction with the subendothelial extracellular matrix: relationship to cancer metastasis.

Dissemination of neoplastic cells within the body involves invasion of blood vessels by tumor cells. This requires adhesion of blood-borne cells to the luminal surface of the vascular endothelium, invasion through the endothelial cell layer and local dissolution of the subendothelial basement membrane. Platelets may participate in each of these steps and thus play a role in the pathogenesis of tumor cell metastasis. To learn more about the possible involvement of platelets we studied the interaction of platelets and tumor cells with cultured vascular endothelial cells and their secreted basement membrane-like extracellular matrix (ECM). Whereas the apical surface of the vascular endothelium lacks adhesive glycoproteins and hence protect the vessel wall against platelet and tumor cell adhesion, the underlying ECM constitute a highly adhesive and thrombogenic surface. Interaction of platelets with this ECM was associated with platelet activation, aggregation and degradation of heparan sulfate in the ECM by means of the platelet heparitinase. The activity of a similar enzyme has been previously correlated with the metastatic potential of various tumor sublines. Biochemical and scanning electron microscopy (SEM) studies have demonstrated that platelets may detect even minor gaps between adjacent endothelial cells and degrade the ECM heparan sulfate. This may expose a larger area of the subendothelium and facilitate subsequent adhesion of blood borne tumor cells. Platelets were also shown to recruit lymphoma cells into minor gaps in the vascular endothelium, that otherwise do not constitute a preferential site of invasion. It is suggested that the platelet heparitinase is involved in the impairment of the integrity of the vessel wall and thus play a role in tumor cell metastasis.

Combined modality treatment for stage III ovarian carcinoma.

Thirty-eight Stage III ovarian carcinoma patients were treated with a combined modality protocol consisting of sequential initial surgery with a maximal tumor reduction, CHAD combination chemotherapy, second look reductive surgery and whole abdominal irradiation. Sixteen patients (42%) had minimal residual tumors (less than 2 cm) after initial surgery (Stage IIIA) and 22 (58%) had large residual tumors (greater than 2 cm) (Stage IIIB). The patients received 3-14 courses of CHAD combination chemotherapy, with a response rate (CR + PR) in the evaluable (Stage IIIB) patients of 91%. Twenty-eight patients had a second attempt of cytoreductive operation (10 Stage IIIA patients and 18 Stage IIIB patients). In 10 patients no residual tumor was found. In another 12 patients residual tumor (less than 2 cm) was found and completely resected, whereas in six patients a complete resection of large residual tumors (greater than 2 cm) was not possible. Twenty-one of the patients also completed a course of whole abdominal radiotherapy. Radiation was well-tolerated with the usual expected amounts of nausea, vomiting, diarrhea and transient leukopenia and thrombocytopenia. 11/21 (52%) of the patients relapsed within the first 18 months after completion of radiotherapy. The actuarial relapse-free survival at 36 months from completions of radiotherapy was 44%. The actuarial survival for the whole group from diagnosis was 43% at 3 years (70% for Stage IIIA and 41% for Stage IIIB). The data indicated that this combined modality protocol is both feasible and well-tolerated but its curative potential for patients with advanced ovarian carcinoma is as yet unknown.

Corticosteroids in radiation-induced pericarditis.

We describe a patient who developed acute pericarditis with effusion six weeks following irradiation of the chest for bilateral carcinoma of the breast. Oral therapy with corticosteroids was rapidly followed by a decrease of the cardiac shadow and by clinical improvement; the pericardial fluid did not reappear during a follow-up period of four years. It seems that acute pericarditis with effusion may appear in the early period after irradiation of the chest and can be treated with corticosteroids.

The management of pericardial effusion in cancer patients.

The relatively little attention given in the literature to the problem of pericardial effusion in patients with cancer reflects the general attitude that if this complication is disclosed, the future of the patient is sealed, and therapy will not change his outcome. We challenge this pessimistic approach, and describe here our experience with seven patients with solid tumors, in whom pericardial effusion was diagnosed; one of them is described in detail. We advocate an active and sometimes even an aggressive therapy, which should always be related to the degree of the hemodynamic impairment. If instant relief is indicated, pericardiocentesis should be done; pericardiectomy is the treatment of choice if the fluid reaccumulates rapidly. After overcoming the urgent problem, the underlying disease and the local pericardial condition should be treated; and in our opinion, a combined approach, such as systemic or local chemotherapy, or both, with or without precordial irradiation, will lead to the optimal result.

Complete heart block following therapeutic irradiation of the left side of the chest.

Two female patients had received therapeutic irradiation of the left side of the chest for adenocarcinoma of the left breast and 18 and 23 years later, respectively, developed atrioventricular block. Both patients had early and late cutaneous reactions, as well as fibrosis of the left lung, lymphedema of the left arm, and pathologic rib fractures but had no signs of recurrence of the carcinoma. One patient developed signs of congestive heart failure while the electrocardiogram revealed second and third degree atrioventricular block; subsequent pacemaker implantation relieved the congestive heart failure. In the second patient, fatigue was the only symptom leading to the diagnosis of transient second and third degree atrioventricular block; this symptom subsided after pacemaker implantation. Based on reports of radiation-induced cardiac damage, it is assumed that the heart block in these two patients might have been due to postirradiation fibrosis of the atrioventricular node, either direct or mediated by fibro-occlusive changes in the coronary vessels.

The effect of estradiol on human myelomonocytic cells. II. Mechanism of enhancing activity of colony formation.

Elevated proportions of monocytes have previously been found in the blood of healthy women during the ovulation period as well as in other conditions associated with increased blood estradiol (E2). This phenomenon was explained, in part, by an augmenting effect which physiological concentrations of E2 may have on the development of granulocyte-macrophage (GM) colonies derived from normal peripheral blood mononuclear cells. To analyze this effect, we tested possible alternatives for the interaction between E2, colony-stimulating factor (CSF) and GM colony progenitor cells. E2 was found not to interact synergistically with CSF, but pre-treatment of the progenitor cells with E2 resulted in higher numbers of colonies in response to CSF. Moreover, E2 did not induce higher secretion of CSF but treatment with anti-CSF antibodies abolished the enhancing effect of E2. Based on these results, we suggest that the augmenting effect of E2 on GM colony formation is mediated by inducing the colony precursor cells to be more responsive to CSF. These findings may help to elucidate some of the complex relationships between estrogens, immune responses and hemopoiesis.

The effect of estradiol on human myelomonocytic cells. 1. Enhancement of colony formation.

Cyclic changes were observed in the content of blood monocytes during the menstrual cycle of normal women. Elevated blood monocytes were found during the ovulation period as well as in other conditions which are associated with increased blood estradiol (E2). To understand the possible association between E2 and monocytosis, we analysed the in vitro effect of E2 on the development of myelomonocytic colonies in culture. E2 in physiological concentrations was found to increase the number of colonies developed from peripheral blood mononuclear cells (PBM) of both females and males. The optimal concentration for the augmenting effect on males' PBM was lower than that for females. Mononuclear cells derived from cord blood, which yielded much higher numbers of colonies than adult PBM, also responded to the stimulatory effect of E2. Estrone and estriol were less effective than E2 in adult PBM. In contrast, progesterone, diethylstilbestrol and testosterone did not affect the number of colonies at the range of physiological concentrations tested. The anti-estrogen Tamoxifen did not inhibit the stimulatory effect of E2. The augmenting effect of E2 on monomyelocytic colony formation may explain at least in part the increase in blood monocyte content of women with high E2 as well as other phenomena of macrophage and granulocyte changes associated with the menstrual cycle.

Levels of fibrinogen/fibrin degradation fragment E and related substances in sera and effusions of patients with malignant disease.

A radioimmunoassay (RIA) was developed and used to determine the level of fragment E [a fibrinogen/fibrin degradation product (FDP)] and of fragment-E-containing substances (FES) in sera and effusion fluids of patients with malignant diseases. Sera of patients with other diseases and sera of healthy individuals served as controls. Results were expressed as units/ml (U/ml), one unit being equivalent to 40 ng pure fragment E. Effusion fluids of both malignant and nonmalignant origin contained relatively high levels of fragment-E-containing substances, up to 7,500 U/ml. Normal sera had less than 30 U/ml, while sera of patients with a variety of neoplastic or nonneoplastic conditions contained larger amounts, reaching to hundreds and, in rare cases (some patients with rheumatoid arthritis), even thousands of U/ml. Some of the highest levels in the malignant sera were found in samples from patients with Burkitt's lymphoma and stomach cancer. About 10%-20% of the reactive material in effusions and 20%-40% in the sera consisted of fragment E. These results confirm earlier findings of high FDP levels in neoplasia. Given the higher accuracy of the radioimmunoassay and its suitability for large scale testing, it would appear worthwhile to continue such studies to explore the clinical usefulness of the RIA for fragment E.

Alveolar rhabdomyosarcoma presenting as subacute intravascular coagulation.

A patient with rhabdomyosarcoma is described in whom the presenting clinical and laboratory features were those of disseminated intravascular coagulation. The patient's rapid downhill course was primarily expressed by haemorrhagic tendency. An alveolar rhabdomyosarcoma, affecting many organs, including vascular and cardiac lumina, was found at necropsy and was considered to be the cause of the consumption coagulopathy.

Adriamycin, vinblastine and mitomycin C as second-line chemotherapy in advanced breast cancer.

Thirty-six evaluable patients with metastatic measurable breast carcinoma previously treated with CMF or CMFVP were given second-line chemotherapy with Adriamycin, vinblastine, and mitomycin C (AVM), as follows: Adriamycin 20 mg/m2 and vinblastine 6 mg/m2 by i. v. push on days 1, 8, and 15, and mitomycin C 10 mg/m2 i. v. on day 1, every 6 weeks. Ten patients (28%) achieved partial remission (PR) lasting a median of 10 months, and eight patients (22%) experienced improvement of a lesser level than PR. An additional nine patients (25%) had disease stabilization; in the remaining nine patients (25%), persistent disease progression was observed. The median survival from the onset of AVM was 7 months for all patients; patients with PR survived a median of 13 months. Myelotoxicity was substantial and frequently interfered with the optimal administration of AVM, especially in patients with skeletal metastases; four patients were hospitalized with leukopenia and fever; all recovered promptly; one death was probably related to thrombocytopenia and CNS bleeding. Our results with AVM are similar to the average response rate published in the literature with the use of Adriamycin as a single agent in previously treated patients with advanced breast cancer.

Treatment of metastatic breast cancer with aminoglutethimide after progression on chemotherapy and/or hormonal therapy with tamoxifen.

Sixty patients suffering from metastatic breast cancer, whose disease progressed on chemotherapy and/or hormonal therapy with tamoxifen, were treated with aminoglutethimide. The overall objective response rate was 33%, including 3% complete responses. The median duration of response was 8 months. Even patients who failed to respond to prior treatment modalities responded objectively to aminoglutethimide. Objective response was observed in all metastatic sites, except for lung. Subjective improvement was achieved in 70% of the patients. Although initial toxicity was high (67%), side effects of aminoglutethimide were transient, and therapy had to be discontinued in only 3 patients. The results of this study indicate that aminoglutethimide in combination with hydrocortisone is a very effective treatment for metastatic breast cancer, especially in patients with positive hormone receptors.

Radiation therapy for locally advanced breast cancer: prognostic factors and complication rate.

A retrospective analysis was carried out in 100 patients with locally advanced breast cancer without distant metastases treated by radiotherapy between 1960 and 1979. The primary tumor was irradiated to a total dose of 60 Gy in 76 patients and to doses ranging between 60 and 80 Gy in 24 patients. The regional lymphatics were treated with doses between 50 and 60 Gy. Following radiotherapy, chemotherapy was administered to 58 patients and hormonal therapy to 29, while 13 patients received no further therapy. Locoregional recurrences were documented in 29% and distant metastases in 49% of patients. The actuarial survival was 56% at 5 years, 21% at 10 years and 14% at 15 years. At 10 years 90% of the surviving patients had some degree of radiation damage.

Prognostic factors affecting treatment results with combination chemotherapy in metastatic breast cancer.

Seventy five patients suffering from metastatic breast cancer previously unexposed to chemotherapy were treated with Cyclophosphamide, Methotrexate and 5-fluorouracil (CMF) upon diagnosis of their first relapse. Dose Level I (85% or more of the planned dose) was given to 14 patients (19%); Dose Level II (66% to 84% of the planned dose) to 29 patients (39%); and Dose Level III (65% or less of the planned dose) to 32 patients (42%). Before initiation of treatment, 41 patients (55%) had a good performance status (PS greater than or equal to 80%) and 34 patients (45%) had a poor performance status (PS less than 80%) according to the Karnofsky scale. The overall response rate was 44%, including 17% complete responses. There was no significant correlation between response rates and the dose levels of chemotherapy. However, patients with a good performance status had a higher response rate (61%) compared with patients with a poor performance status (25%; p = 0.0025). The actuarial 3 year survival according to dose levels of CMF was 15%, 41% and 36% for Dose Levels I, II, and III, respectively (p = 0.34), but was 52% for patients with PS greater than or equal to 80% versus 14% for patients with PS less than 80% (p = 0.0001). These data indicate that the general condition of the patient at the time of initiation of CMF chemotherapy, as reflected by the performance status, may be of greater significance for the prediction of the ultimate treatment outcome rather than the total amount of chemotherapy delivered per se.

Aminoglutethimide as second line endocrine therapy in advanced breast cancer.

Eighty five patients suffering from metastatic breast cancer, whose disease progressed on hormonal therapy with tamoxifen, were treated with aminoglutethimide. The overall objective response rate was 33%, with a median duration of response of 8 months. Even patients who failed to respond to tamoxifen responded to aminoglutethimide. Objective response was achieved in all metastatic sites, except for lung. Subjective improvement was observed in 75% of the patients. In spite of the fact that initial toxicity was high (70%), side effects of aminoglutethimide were transient, and treatment had to be discontinued in only 4 patients. The results of this trial indicate that aminoglutethimide is an important addition for the treatment of metastatic breast cancer, especially in patients with positive hormone receptors.

Adjuvant chemotherapy with and without radiotherapy in stage II breast cancer.

The influence of several variables on the effectiveness of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy given to 87 patients with stage II breast cancer was retrospectively analyzed. CMF was given in optimal doses (greater than or equal to 85% of the planned dose) to 17% of the patients; in intermediate doses (66-84% of the planned dose) to 50% of the patients; and in low doses (less than or equal to 65% of the planned dose) to 33% of the patients. Radiotherapy before CMF was given to 68% of the patients; simultaneous radio- and chemotherapy to 17% of the patients; and the remaining 15% received CMF only. At a median follow-up of 8 yr, 61% of the patients were still alive; 54% of them were disease-free. Patients receiving radio- and chemotherapy concomitantly had a higher relapse-free survival (RFS) than those given both treatments sequentially (77% versus 46%; P = 0.05). Dose levels of CMF did not influence RFS. Delay in initiation of CMF, mainly due to the administration of prior radiotherapy was deleterious: patients started on CMF within 3 months of diagnosis had a 77% 8 yr RFS, as compared with 44% for those with a delay of over 3 months (P = 0.01). No differences in local relapse rates were observed between irradiated and non-irradiated patients, although 87% of all distant failures occurred in patients who received radio- and chemotherapy sequentially. The data of this study indicate that delay in onset of CMF is deleterious, and can be avoided by the simultaneous administration of both treatment modalities, since this approach was well tolerated, without significant myelotoxicity.

Characterization of prolactin receptors and their distribution among American and Israeli women with breast cancer: implications for prediction of hormonal dependency and treatment.

A micro-method is reported for the determination and characterization of prolactin (PRL) receptors in human breast cancer specimens using either intact biopsy tissue or the pellet fraction remaining from biopsies previously processed for steroid hormone receptors. Labeled human PRL is used as the ligand. The specific PRL-binding of 307 human breast cancer specimens was evaluated by this micro-method. A significant level of specific PRL-binding (3-25 fmol per mg membrane protein) was detected in 41% of US breast cancer patients and 42% of Israeli patients. Scatchard analyses, performed on pooled membrane fractions with the highest specific PRL-binding revealed one class of receptors having a dissociation constant, Kd = 4.1 x 10(-9), and specific binding capacity, Bmax = 1.3 pmol per mg protein. These preparations were exposed to 3 M MgCl2, which dissociates the endogenous-bound PRL from the hormone-receptor complex and allows the characterization of the "total" PRL receptors. Two classes of receptors were then revealed. One class of receptors showed high affinity (Kd1 = 8.1 x 10(-10) M) and low capacity (Bmax1 = 335 fmol per mg protein), while the other possessed lower affinity (Kd2 = 8.2 x 10(-8) M), but a higher capacity (Bmax2 = 34.4 pmol per mg protein). Since PRL facilitates the growth of human breast cancer cell lines, these results indicate that a high proportion of human breast cancers may be PRL dependent. Routine determination of PRL receptors in biopsies of human breast cancer may permit the selection of a better treatment, since it is possible that the reduction in PRL levels could inhibit those tumors which are prolactin dependent.