Regulation of macrophage tumoricidal function: a role for prostaglandins of the E series.

Exogenously added prostaglandins E1 and E2, but not F2alpha, inhibited the tumoricidal activity of interferon-activated macrophages of mice. A role for adenosine 3',5'-monophosphate (cyclic AMP) in modulating macrophage functional activity was suggested because prostaglandins of the E series increase intracellular concentrations of cyclic AMP in macrophages and because treatment of interferon-activated macrophages with dibutyryl cyclic AMP consistently inhibits expression of cytotoxicity. Since the activated macrophage releases high concentrations of prostaglandin E2, it is postulated that this prostaglandin could act locally in negative feedback inhibition to limit cell activities.

Effects of adriamycin and cyclophosphamide treatment on induction of macrophage cytotoxic function in mice.

The effects of i.p. and s.c. Adriamycin and cyclophosphamide treatment of BALB/c x DBA/2F1 mice were studied alone and in combination with immunotherapeutic agents, pyran copolymer and Bacillus Calmette-Guérin, on macrophage cytotoxic ability, As assessed by direct viable cell counts of MBL-2 leukemia cells, both Adriamycin and cyclophosphamide produced growth-inhibitory macrophages. This function after s.c. cytostatic treatment peaked at Day 1 and decreased progressively, attaining normal control values by Day 6. When adjuvants, such as pyran and B. Calmette-Guérin, were administered i.p. simultaneously with s.c. Adriamycin or cyclophosphamide, adjuvant-induced cytotoxic function was not markedly affected. A better knowledge of the influence of cytostatic agents alone or combined with immunoadjuvants on macrophage cytotoxic ability may be useful in designing more effective chemoimmunotherapy protocols.

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

Diffuse fasciitis with eosinophilia. A clinicopathologic study.

Three cases of diffuse fasciitis with eosinophilia are presented, and their clinical, laboratory and histologic follow-up are outlined. Furthermore histologic comparison with scleroderma is attempted and the literature is reviewed. From our findings, we conclude that diffuse fasciitis with eosinophilia is a distinct clinicopathologic entity.

A phase II trial of carboplatin and vindesine in patients with non-small cell lung cancer. A Hellenic Cooperative Oncology Group study.

In an effort to investigate a regimen less toxic and more convenient than cisplatin combinations, 50 patients with non-small cell lung cancer (NSCLC) were treated in a Phase II study with carboplatin and vindesine. Carboplatin 300 mg/m2 every 28 days and vindesine 3 mg/m2 every 2 weeks were administered on an outpatient basis. Eight patients had a partial response of their disease (16%, confidence limits 7-29%). Mean duration of response was 4.5+ months (1 +/- 8). Toxicity, mainly of grade I-II, was noticed in 4-28% of the patients. The most common side effect was mild to moderate leukopenia (28%). The combination of carboplatin and vindesine at the above doses was very well tolerated. Although the response rate was relatively low, the survival in this patient population was similar to other cisplatin-containing regimens.

Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature.

Endobronchial metastases (EBM) secondaries to extrapulmonary solid malignant tumors are rare. Breast, colon and renal adenocarcinomas are the most frequent tumors associated with EBM. Since 1990 we have treated eight patients with EBM secondary to renal adenocarcinoma (three cases), colon adenocarcinoma (two cases), gastric adenocarcinoma (one case), bladder carcinoma (one case) and basal cell carcinoma (one case). Endobronchial lesions were detected by bronchoscopy and their metastatic nature was confirmed histopathologically in all eight cases. We also conducted a review of EBM reporting studies published in English language. The median interval from the diagnosis of the primary tumour was 41 months. Symptoms and radiological findings were indistinguishable from those of primary lung cancer. Five patients were treated with external radiotherapy with symptomatic improvement while two patients had chemotherapy and one patient underwent surgical resection of the metastasis. Systemic treatment was used in six cases with no significant effect on EBM. Median survival after EBM diagnosis was 9 months with one patient surviving 3.5 years and two patients still alive at 1 year. In conclusion, EBM usually represent a late manifestation requiring differential diagnosis from a primary lung cancer. Local treatment may result in symptomatic improvement but prognosis is generally poor averaging 1-2 years in most series.

Mitoxantrone: an active new agent in the treatment of advanced breast cancer.

Sixty-five patients with advanced breast carcinoma were treated with mitoxantrone, an anthracenedione with structural similarities to adriamycin. The series included 26 patients who had received no prior chemotherapy. Treatment was given in a dose of 12-14 mg/m2 by IV infusion, repeated every 3 weeks. Sixty-two patients were evaluable for response, but all were evaluable for toxicity. One (2%) achieved a complete response and 18 (29%) a partial response (overall response rate 31%). The response rate in patients who had received no prior chemotherapy was 35%, vs 22% in previously treated patients. The median duration of response was 10 months (range 3.5-18.5 months). Two responders had previously failed to respond to adriamycin, and a third responder subsequently failed to respond to adriamycin. Neutropenia was the most frequently seen toxicity, with a WBC of less than 2,000/mm3 seen in 26 patients (40%), eight of whom (12%) had a neutropenic infection. Thrombocytopenia (less than 100,000/mm3) occurred in 12 patients (18%), but in three of these only after at least 6 months of treatment. Two patients developed readily reversible cardiac failure after prolonged treatment (11-13 months). Other toxicities were in general mild, and the drug was well tolerated: severe alopecia occurred in only one patient. Mitoxantrone is an active well-tolerated agent in the treatment of advanced breast carcinoma, but the risk of neutropenia requires careful supervision. The long-term risk of cardiotoxicity cannot yet be fully assessed.

Interdigitating Reticulum Cell Sarcoma Positive immunohistochemistry for HLA-DR and two other activation antigens, CD30(Ki-1) and CD25(IL2R).

This communication reports a case of the rare interdigitating reticulum cell (IDRC) sarcoma of lymph nodes in a 46-year-old man. Extensive immunophenotypic analysis on paraffin and frozen sections revealed positivity on the neoplastic cells for protein S-100 as well as for antigens CD1, HLA-DR, CD4, CD25 (IL2R) and CD30 (Ki-1). The simultaneous positivity for the three activation antigens CD30, HLA-DR, and IL2R, a phenomenon mostly described in H and S-R cells of Hodgkin's disease, is discussed in particular.

Cutaneous lymphocytic vasculopathy in lymphoproliferative disorders--a paraneoplastic lymphocytic vasculitis of the skin.

In this report the histopathology and the natural history of cutaneous lymphocytic vasculopathy (lymphocytic vasculitis) in patients with lymphoproliferative diseases, is described. Between January 1986 and June 1992, 116 patients with non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemias (CLL) were followed. Among them 3 patients with NHL, one with angioimmunoblastic lymphadenopathy/lymphoma and 7 with CLL developed cutaneous vasculitic changes during the course of their disease (incidence of 9.5%). All patients had advanced stage disease. Lymphomas were of B-cell origin and either low or intermediate grade. The median time between the diagnosis of NHL or CLL and the appearance of skin manifestations was 18 months. Recurrent vasculitic changes involving exclusively the skin, was characterized by a (maculo)papular rash, most commonly found in the upper and lower extremities. Pruritus of varying intensity was present in 82% of the patients. In the biopsy, all had perivascular and/or vessel wall lymphocytic infiltration of the dermis with occasional red cell extravasation. Immunohistochemical staining revealed that these infiltrates were mainly composed of T-lymphocytes. We conclude, that cutaneous lymphocytic vasculopathy is a relatively common paraneoplastic skin manifestation in patients with lymphoproliferative diseases and histologically is characterized as lymphocytic vasculitis with (peri)vascular infiltration by non-malignant T lymphocytes.

Extraskeletal Ewing's sarcoma. Presentation of two cases and review of the literature.

We present here two cases of extraskeletal Ewing's sarcoma, the first in a 50-year-old female and the second in a 25-year-old male. We discuss the clinical picture, histopathology and therapeutic management. The literature is also reviewed, with major emphasis on the treatment of this rare disease.

Neglected cases of papillary and follicular thyroid carcinoma. Occurrence of subcutaneous scalp metastases.

Three cases, two follicular and one of papillary thyroid carcinoma are reported. All three patients presented with subcutaneous cystic scalp metastases; they had a long-standing history of thyroid cancer, although two had never sought medical attention. We discuss this unusual clinical manifestation in patients with untreated well differentiated thyroid carcinoma.

Monoclonal immunoglobulins and autoantibodies in lymphoid malignancies.

The presence of serum monoclonal or oligoclonal immunoglobulins (paraproteins) was investigated in 38 non-Hodgkin's lymphoma and chronic lymphocytic leukemia patients, 33 patients with solid tumors and 33 healthy individuals. Seventy two percent of non-Hodgkin's lymphoma and 31% of chronic lymphocytic leukemia patients had serum paraproteins, in contrast to 21% and 15% of solid tumor patients and normal controls respectively. There was no significant prevalence of a certain isotype or light chain in the non-Hodgkin's lymphoma, chronic lymphocytic leukemia and solid tumor groups. In the healthy individuals all bands were monoclonal of the IgG isotype. No correlation was found between histologic grading of lymphoid malignancy or disease stage and serum monoclonality. No serologic or histologic autoimmune features were demonstrated in non-Hodgkin's lymphoma and chronic lymphocytic leukemia patients. In addition, no correlation was found between serum autoantibody activity and mono- or oligoclonal immunoglobulins.

Serum soluble interleukin-2 receptors in epithelial ovarian cancer patients.

The levels of soluble interleukin-2 receptors (sIL-R2) were measured in the serum of 52 patients with epithelial ovarian carcinoma as well as in 25 age and sex-matched normal controls. The mean serum level of sIL-R2 was increased in 37 patients (71.2%). Comparison of these levels to those of normal controls showed a highly statistically significant difference (p < 0.001). Serum sIL-R2 levels were not related to histology, clinical stage or the presence of ascites (p = 0.58, p = 0.32 and p = 0.67, respectively), nor did they follow disease activity or response to chemotherapy. However, patients with higher pretreatment sIL-2R levels (more than 1200 U/ml) were found to have a longer survival (p < 0.02), possibly explained by the presence of activated lymphocytes and a better immune surveillance. We conclude that the serum level of sIL-R2: a) is elevated in ovarian cancer patients, b) has no relationship with histological subtypes, tumor burden or the presence of ascites, c) cannot serve as a valuable tumor marker for the monitoring of patient treatment, and d) has a prognostic value for survival.

High-dose epirubicin as a single agent in the treatment of patients with advanced breast cancer. A Hellenic Co-operative Oncology Group study.

Fifty-two women with advanced breast cancer were treated with 6 cycles of epirubicin. Even though the study was started with a dose schedule of 110 mg/m2 every 3 weeks, the average treatment interval was 26 days and the median weekly dose 78% of the protocol requirement. Forty-eight patients were evaluable for response; 3 achieved a complete remission which lasted for 17, 24 and 65 weeks, respectively, and 14 a partial remission. Median survival was 32 weeks. Toxicity included nausea/vomiting (68%), anemia (24%), leukopenia (37%), thrombocytopenia (8%), alopecia (81%), stomatitis (24%), diarrhea (14%), fever (19%) and fatigue (14%). Also 1 treatment-related death occurred and 2 cases of arrhythmia. Monotherapy with high doses of epirubicin has definite activity in advanced breast cancer and deserves further study in combination with hematopoietic growth factors which might allow a higher dose intensity.

[The natural course of primary Sjögren's syndrome (a clinical study)]. / Estestvennoe techenie pervichnogo sindroma Shegrena (klinicheskoe issledovanie).

In this work the authors analyzed the clinical course and diagnostic procedures of 104 patients with primary Sjogren's syndrome (pSS): 57 patients diagnosed and followed-up at Ioannina University and 47 similar patients treated at the National Institute of Health (USA). Both studies have shown that pSS is predominantly a female disease with a latent period of 6-8 yrs from the time of the first symptom to the time of final diagnosis. Although the syndrome begins almost exclusively with glandular manifestations (xerostomia, xerophthalmia or parotid gland enlargement), in a respectable percentage of patients it eventually progresses to extraglandular involvement. pSS can be potentially complicated by benign (pseudolymphoma) or malignant (lymphoma) lymphoproliferative disorders.

Clear-cell sarcoma of tendons and aponeuroses: a clinicopathologic study. Presentation of six additional cases with review of the literature.

Clear-cell sarcoma of tendons and aponeuroses is a rare and slowly growing soft tissue sarcoma, affecting mainly young adults. During the last 15 years, approximately 60 cases have been reported in the literature. In this report, six additional cases followed in the Sarcoma Unit at The Royal Marsden Hospital are presented, representing approximately 1% of the total number of sarcomas treated in our unit between 1972 and 1982. A review of the literature has also been included.

Lymphoma in Sjogren's syndrome.

Sjogren's syndrome is an autoimmune disease with a known predisposition for lymphoma development. Eight of 120 patients with primary Sjogren's syndrome followed at the University of Ioannina over the past 7 years developed non-Hodgkin's lymphoma diagnosed according to the Kiel classification. The lymphomas differed by location and grading. Six were called low grade (immunocytoma) and two intermediate grade non-Hodgkin's lymphomas. Five of the immunocytomas involved the minor salivary or lacrimal glands. Immunoperoxidase staining for light chains revealed monoclonal populations. Two patients showed spontaneous regression not previously reported in Sjogren's syndrome. Thus, in Sjogren's syndrome, low grade non-Hodgkin's lymphomas and especially immunocytomas are the most common lymphomas. These lymphomas tend to evolve very slowly and may regress spontaneously. Given these facts, a conservative approach to treatment is indicated in those patients with only localized disease.

Serum-soluble interleukin-2 receptors in B-cell lymphoproliferative malignancies.

The levels of soluble interleukin-2 receptors (sIL-2R) were determined in the serum of 53 patients with B-cell lymphoproliferative malignancies, including 31 patients with non-Hodgkin lymphomas (NHL), 16 with chronic lymphocytic leukemia (CLL), and 6 with multiple myeloma. In addition, serum samples from 40 patients with various solid tumors as well as from 53 healthy individuals were used as controls. It was found that the mean serum levels of sIL-2R were significantly increased (P less than 0.001) in NHL (mean +/- standard error of the mean 2,327 +/- 320 units/ml) and CLL patients (2517 +/- 451 units/ml) as compared to normal controls (207 +/- 17 units/ml). No such difference was observed when the serum sIL-2R levels of patients with multiple myeloma or solid tumors were analyzed. Serum sIL-2R levels were closely related to the clinical stage, the presence of B-symptoms, and the disease activity of patients with NHL and CLL. In fact, response to chemotherapy was followed by marked decrease or normalization of sIL-2R levels, while in a number of patients sIL-2R values were even able to predict disease relapse. Finally, no association with histologic grade in NHL patients, could be demonstrated. We conclude that serum sIL-2R (1) are increased only in B-NHL and B-CLL but not in myeloma patients, (2) are related to the tumor burden, and (3) can serve as a valuable tumor marker for the monitoring of patients treatment.

Macrophage activation and antitumor activity of a Brucella abortus ether extract, Bru-Pel.

Bru-Pel and Brucella abortus lipopolysaccharide (LPS) were tested for both macrophage activation and antitumor activity in an artificial metastasis model. Resting macrophages were rendered nonspecifically tumoricidal for MBL-2 lymphoblastic leukemia target cells by exposure to Bru-Pel at greater than or equal to 1 ng/ml of culture medium. B. abortus LPS failed to activate macrophages in vitro at all concentrations tested. Ip treatment of homozygous nude mice with Bru-Pel induced cytotoxic macrophages, indicating that Bru-Pel activated macrophages through a thymic-independent process. An artificial metastasis model was developed where single-cell suspensions of Madison 109 lung carcinoma were inoculated iv into syngeneic BALB/c mice. Bru-Pel, but not B. abortus LPS, strikingly inhibited tumor-colony formation in the lungs. Although Bru-Pel contains endotoxin, the data demonstrate that endotoxin is apparently not the active component by which Bru-Pel activates macrophages and enhances host resistance to cancer.