Stromal coexpression of uPA/PAI-1 protein predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer.

BACKGROUND: To evaluate whether uPA/PAI-1 protein in hormone receptor-positive (HR+) breast tumor can predict prognosis in early breast cancer (BC). METHODS: 606 women with HR + BC who had ≥5 years of endocrine therapy and in whom tumor tissue was available were included in this analysis. Stromal uPA/PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). RESULTS: Stromal uPA was detected in 292/538 tumors (54.3%) while 269/505 samples (53.3%) exhibited stromal PAI-1. Co-expression of both proteins was found in 163/437 (37.3%) samples. Stromal uPA/PAI-1 co-expression was not associated with tumor size, age, nodal status, grading, or receptor status. Tumor stroma with both uPA and PAI-1 protein expression were more likely to have a shorter DRFS (HR: 1.87; 95%CI 1.18-2.96; p = 0.007) and OS (HR: 1.29; 95%CI 0.93-1.80; p = 0.129) than women without uPA/PAI-1 co-expression. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DRFS (86.5% vs 72.4%; p < 0.001) and OS (70.4% vs 58.9%; p = 0.020) compared to women with uPA/PAI-1 negative tumors. CONCLUSION: Stromal co-expression of uPA and PAI-1 in breast cancer predicts poor DRFS and OS in postmenopausal women with HR + early-stage BC who receive endocrine therapy.

Long-term cardiovascular complications in stage I seminoma patients.

PURPOSE: The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. METHODS: This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. RESULTS: During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). CONCLUSION: We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation.

Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner.

BACKGROUND: Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K(+) channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients. METHODS: In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced. Subsequently, selected cardinal neoplasia associated cellular parameters were assessed and compared. RESULTS: Adhesion to fibronectin coated surface as well as cell proliferation remained unaffected. Other vital parameters intimately linked to malignancy, i.e. wound healing, chemoinvasion, cellular velocities / motilities and angiogenesis were massively affected by GIRK1 overexpression. Overexpression of different GIRK1 splice variants exerted differential actions. While GIRK1a and GIRK1c overexpression reinforced the affected parameters towards malignancy, overexpression of GIRK1d resulted in the opposite. Single channel recording using the patch clamp technique revealed functional GIRK channels in the plasma membrane of MCF-7 cells albeit at very low frequency. DISCUSSION: We conclude that GIRK1d acts as a dominant negative constituent of functional GIRK complexes present in the plasma membrane of MCF-7 cells, while overexpression of GIRK1a and GIRK1c augmented their activity. The core component responsible for the cancerogenic action of GIRK1 is apparently presented by a segment comprising aminoacids 235-402, that is present exclusively in GIRK1a and GIRK1c, but not GIRK1d (positions according to GIRK1a primary structure). CONCLUSIONS: The current study provides insight into the cellular and molecular consequences of KCNJ3 overexpression in breast cancer cells and the mechanism upon clinical outcome in patients suffering from breast cancer.

MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients.

BACKGROUND: MicroRNAs (miRNAs) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled miRNAs associated with E-cadherin expression in CRC cells in an attempt to identify miRNAs that are associated with aggressive clinical course in CRC patients. METHODS: Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for differences in abundance for more than 1000 human miRNAs using microarray technology. One of the most differentially expressed miRNAs, miR-200a was evaluated for its prognostic role in a cohort of 111 patients and independently validated in 217 patients of the Cancer Genome Atlas data set. To further characterise the biological role of miR-200a expression in CRC, in vitro miR-200a inhibition and overexpression were performed and the effects on cellular growth, apoptosis and epithelial-mesenchymal transition (EMT)-related gene expression were explored. RESULTS: In situ hybridisation specifically localised miR-200a in CRC cells. In both cohorts, a low miR-200a expression was associated with poor survival (P<0.05). Multivariate Cox regression analysis identified low levels of miR-200a expression as an independent prognostic factor with respect to cancer-specific survival (HR=2.04, CI=1.28-3.25, P<0.002). Gain and loss of function assays for miR-200a in vitro led to a significantly differential and converse expression of EMT-related genes (P<0.001.) A low expression of miR-200a was also observed in cancer stem cell-enriched spheroid growth conditions (P<0.05). CONCLUSIONS: In conclusion, our data suggest that low miR-200a expression is associated with poor prognosis in CRC patients. MiR-200a has a regulatory effect on EMT and is associated with cancer stem cell properties in CRC.

The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy.

OBJECTIVES: To date, no reliable markers are available to predict response to or to assess prognosis after preoperative systemic chemotherapy (PST) in patients with locally advanced breast cancer. Previous studies demonstrated that elevated levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, are associated with higher risk for metastatic disease and poor prognosis in various tumor types. We, therefore, hypothesized that serum sE-cadherin levels measured before PST may correlate with pathological response. DESIGN AND METHODS: In a retrospective analysis, sE-cadherin levels were measured in sera of 108 female patients with histologically proven breast cancer before initiation of PST by using a commercially available quantitative sandwich enzyme immunoassay technique. Patients received a median number of 4 (range 3-6) cycles of anthracyline-based chemotherapy. The median patient age was 51.5 (range 21-71) years. Tumor size was measured clinically and translated into the tumor-node-metastasis (TNM)-system before the start of chemotherapy. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score. In univariate analyses the correlations between levels of sE-cadherin and pathological response to PST were calculated. RESULTS: The histopathological regression scores correlated significantly with tumor grading (p=0.045), clinical lymph node status before PST (p=0.031) and sE-cadherin levels (p=0.039). No correlation was seen between histopathological regression scores and hormone receptor and menopausal status as well as Her2-neu status. CONCLUSION: sE-cadherin may be a marker predicting response to PST for patients with breast cancer. Our findings warrant further evaluation of sE-cadherin in a prospective trial.

Prolactin receptor is a negative prognostic factor in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: The influence of human prolactin (hPRL) on the development of breast and other types of cancer is well established. Little information, however, exists on the effects of hPRL on squamous cell carcinomas of the head and neck (SCCHNs). METHODS: In this study, we evaluated prolactin receptor (PRLR) expression in SCCHN cell lines and assessed by immunohistochemistry the expression in 89 patients with SCCHNs. The PRLR expression was correlated with clinicopathological characteristics as well as clinical outcome. The effect of hPRL treatment on tumour cell growth was evaluated in vitro. RESULTS: Immunoreactivity for PRLR was observed in 85 out of 89 (95%) tumours. Multivariate COX regression analysis confirmed high levels of PRLR expression (>25% of tumour cells) to be an independent prognostic factor with respect to overall survival (HR=3.70, 95% CI: 1.14-12.01; P=0.029) and disease-free survival (P=0.017). Growth of PRLR-positive cancer cells increased in response to hPRL treatment. CONCLUSION: Our data indicate that hPRL is an important growth factor for SCCHN. Because of PRLR expression in a vast majority of tumour specimens and its negative impact on overall survival, the receptor represents a novel prognosticator and a promising drug target for patients with SCCHNs.

Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours?

AIM: To determine the platelet-derived growth factor (PDGF) alpha and beta status of desmoid tumours. Desmoid tumours are rare monoclonal neoplasms that appear to have no metastatic potential. Surgical resection and radiotherapy in the event of a positive surgical margin is the first-line treatment. Recurrences are frequent. Treatment results using non-steroidal anti-inflammatory agents, anti-oestrogen compounds and other agents such as Imatinib mesylate have been published. Therapy with Imatinib has been proposed as a therapeutic option, although in most reports desmoid tumours are reported to be c-kit-. METHODS AND RESULTS: We performed immunohistochemical analysis on 124 archived samples (85 patients) of desmoid tumours using antibodies to PDGFalpha, PDGFbeta, PDGFRalpha and PDGFRbeta. All desmoid tumours showed immunoreactivity with antibodies to PDGFalpha and PDGFRalpha, whereas with antibodies to PDGFbeta and PDGFRbeta no specific reaction could be detected. Mutational analysis of PDGFRalpha (exons 11, 12, 17 and 18) and PDGFRbeta (exon 12) on frozen material from 14 patients was performed, but no mutations leading to amino acid changes in the mature protein were identified. CONCLUSION: The absence of an activating mutation in a protooncogene does not exclude the efficacy of tyrosine kinase inhibitors through other possible mechanisms, and these might be a therapeutic option for patients with desmoid tumours in whom established local and systemic approaches fail to control the disease.

Recurrent endometrial stromal sarcoma after treatment with high-dose chemotherapy and autologous stem-cell support: A case report.

INTRODUCTION: The efficacy of high-dose chemotherapy plus transplantation of autologous hematopoetic stem cells in patients with endometrial stromal sarcomas is unknown. CASE REPORT: A 39-year-old woman with Stage III endometrial stromal sarcoma (ESS) underwent radical surgery, followed by five courses of ifosfamide, adriamycin and dacarbazine postoperatively. Six months after primary surgery stem cell priming was performed. Five months later bone marrow was aspirated and high-dose chemotherapy with carboplatin, vepeside and holoxan were administered after which bone marrow was retransfused. Seven years after primary surgery the patient developed an abdominal recurrence which was removed surgically and adjuvant radiotherapy was administered. One year later the patient underwent hemicolectomy because of a new recurrence infiltrating the ascending colon. Treatment with 25 mg exemestane was begun. The patient is currently alive and free of disease nine years after the initial diagnosis. CONCLUSION: Aggressive chemotherapy with autologous stem-cell support seems to be ineffective in patients with ESS.

Acute pseudo-obstruction of the small intestine following high-dose chemotherapy and stem cell support.

BACKGROUND: Acute intestinal pseudo-obstruction is a potentially life-threatening disease which is characterized by massive dilation of the colon or small intestine without mechanical obstruction and may develop after surgery or severe illness. PATIENTS AND METHODS: We report 2 cases in which acute small intestinal pseudo-obstruction occurred after high-dose chemotherapy and autologous stem cell support. In 1 patient explorative abdominal laparoscopy was performed to rule out mechanical ileus. However, after having initiated treatment with acetylcholinesterase inhibitors a prompt small intestinal decompression was observed in both patients. CONCLUSIONS: Acetylcholinesterase inhibitors should be considered as an early conservative intervention in the treatment of acute intestinal pseudo-obstruction to avoid surgery of patients undergoing high-dose chemotherapy with autologous stem cell support.

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer.

Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P<0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P<0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P<0.0001 and <0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P<0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.

Combined treatment of metastatic osteosarcoma of the spine.

We report on a 28-year-old male with a single metastasis of an osteosarcoma in the twelfth thoracic vertebra occurring 9 years after initial diagnosis of the primary tumour in the left distal femur and neoadjuvant treatment according to a modified T-10 protocol. After pre-operative second-line combination chemotherapy with doxorubicin, carboplatin and etoposide leading to regression of the primarily inoperable metastasis wide resection of the tumour employing total spondylectomy was done. The duration of response had been 65 months since the end of subsequent postoperative chemotherapy with the same regimen.

A double-blind randomized-phase II trial comparing immunization with antiidiotype goat antibody vaccine SCV 106 versus unspecific goat antibodies in patients with metastatic colorectal cancer.

This article reports on the first double-blind randomized clinical study with an antiidiotype antibody vaccine in patients with metastatic colorectal carcinoma. The study was performed to determine immunological parameters, efficacy, and tolerability of the vaccine. Forty-two patients with metastatic colorectal cancer were randomly assigned to multiple immunizations with goat IgG antiidiotype vaccine SCV 106 (n = 21) or unspecific goat IgG as controls (n = 21). The antiidiotype vaccine mimicked the 17-1A glycoprotein antigen associated with colorectal cancer. Of the 42 patients entered, 39 were evaluable for efficacy (SCV 106, n = 18; controls, n = 21). Twenty-nine patients raised antibodies to the vaccines (immunological responders, SCV 106, n = 12; controls, n = 17). Only in the SCV 106 group was a significant increase (p = 0.002) of titers with specificity of antitumor antibody 17-1A found. According to the International Union Against Cancer (UICC) criteria no tumor response was observed. However, in the SCV 106 group the relative increase of carcinoembryonic antigen (CEA) levels between entry and observed disease progression was lower (p = 0.03) and disease progression was determined less frequently by development of new metastases (p = 0.001). On an intention-to-treat basis, the survival time difference between the two groups was not significant. Comparison of immunological responders in both groups revealed a significant survival advantage of the SCV 106-treated patients compared with controls (mean 67 versus 39 weeks; p = 0.01). Immunizations were well tolerated. Vaccination of immunologically responding metastatic colorectal carcinoma patients with SCV 106 leads to slowed disease progression and tumor dissemination and significantly prolongs survival time.

Soluble CD44 v5 and v6 in serum of patients with breast cancer. Correlation with expression of CD44 v5 and v6 variants in primary tumors and location of distant metastasis.

Primary breast cancers were shown to overexpress CD44 v5 and v6 at the plasma membrane. However, the clinical significance of this overexpression remains unclear. Overexpression of CD44 v5 and v6 in primary breast cancers was found to correlate with metastasis and poor prognosis by some investigators, yet this correlation could not be confirmed by others using different antibodies. In this study the influence of metastatic disease, the site of metastasis, and the amount of CD44 v5 and v6 expression in the primary tumor on serum levels of the soluble forms of CD44 v5 and v6 (sCD44 v5 and v6) in breast cancer patients was investigated. Soluble CD44 v5 and v6 serum levels were measured by enzyme linked immuno sorbent assay in a group of breast cancer patients who developed metastases in various organs and in another group of patients with single organ metastasis. For control, sCD44 v5 and v6 levels were measured in breast cancer patients who remained free of metastasis and in healthy blood donors. Expression of plasma membrane bound CD44 v5 and v6 in the primary tumors of the patients with metastasis in various organs was correlated to sCD44 v5 and v6 levels in serum. Furthermore the size of sCD44 v6 was analyzed by immunoblot using a monoclonal antibody directed against CD44 v6. When metastases were detected, sCD44 v5 and v6 serum levels were increased as compared to levels measured one month after tumor surgery in patients free of metastases (p= 0.0025 and p=0.0004). Six of 19 and 6 of 20 patients had sCD44 v5 and v6 serum levels above a cut-off level of 85 and 275 ng/mL, respectively. In these cases expression of CD44 v5 and v6 in the primary cancers was also elevated. Low sCD44 v5 and v6 serum levels were associated with weak expression of CD44 v5 and v6 in the respective primary cancers. As shown by statistical analysis of sCD44 v5 and v6 levels in 57 patients with single organ metastases, elevated sCD44 v6 levels but not sCD44 v5 levels were associated with metastases in liver or bone (p=0.0025). Immunoblot analysis of soluble CD44 proteins in serum revealed two CD44 v6 specific signals of approximately 120 and 170 kDa. Increased sCD44 v5 and v6 serum levels in patients with breast cancer were influenced by the amount of CD44 v5 and v6 expression in the primary tumor by the site of metastasis. Elevated sCD44 v6 serum levels were preferentially found in patients with metastases in liver or bone.

Sequential treatment of recurrent mesenteric desmoid tumor.

BACKGROUND: The optimal management of inoperable desmoid tumors is still unclear. We report a 26 year-old female patient with familial adenomatous polyposis suffering from a recurrent inoperable intraabdominal desmoid tumor and its sequential treatment. METHODS: Treatment strategies included low-dose tamoxifen (30 mg orally per day), high-dose tamoxifen (90 mg orally per day), and a subsequent combination of goserelin acetate (3.6 mg subcutaneously once every four weeks) plus low-dose tamoxifen, medroxyprogesterone acetate (1000 mg orally per day) and interferon gamma (3 Mio IU subcutaneously 3 times a week). RESULTS: The combination of goserelin acetate and low-dose tamoxifen resulted in a decrease in tumour size and a complete relief of symptoms for 17 months. Thereafter the tumor progressed and again growth was stopped with interferon gamma therapy for another 6 months. All other treatment modalities had no effect. CONCLUSIONS: This study demonstrates long-term regression of a desmoid tumor with combined endocrine therapy using goserelin acetate plus tamoxifen. Tumor progression after 17 months was again stopped by a combination of interferon-gamma and goserelin acetate.

Recombinant human erythropoietin for the correction of cancer associated anemia with and without concomitant cytotoxic chemotherapy.

BACKGROUND: Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied. METHODS: One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter. RESULTS: Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients. CONCLUSION: This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.

A phase II trial of weekly high-dose folinic acid and 5-fluorouracil in combination with epirubicin as salvage chemotherapy in advanced breast cancer.

Twenty-five patients with advanced breast cancer (ABC) who had failed from first-line chemotherapy entered into a phase II study employing weekly 5-fluorouracil (FU) 350 mg/m2, folinic acid (FA) 500 mg/m2, and epirubicin (EPI) 35 mg/m2, for a maximum of 18 cycles. Twenty-three patients were evaluable for response. One achieved a complete response and 7 showed a partial response, for an objective response rate of 35%; 7 (31%) patients achieved a stabilization of the disease, while 8 (35%) patients progressed under treatment. The median duration of response was 6 months and median survival amounted to 10.6 months. Side effects were in general mild with grade III leukopenia in 5 patients and grade IV leukopenia in 1 patient. Other toxicity included nausea and vomiting (88%), diarrhea (26%), stomatitis (40%) and alopecia (84%), but all of them mainly restricted to WHO grade I and II. Our results suggest that the combination of high-dose FA, FU, and EPI can be safely administered in the investigated schedule and represents an attractive alternative in the search for second-line therapies that combine effectiveness with acceptable toxicity in the treatment of refractory ABC.

[Breast cancer in the man: a report of 30 patients]. / Das Mammakarzinom des Mannes: Ein Bericht über 30 Patienten.

A retrospective review of male patients suffering from breast cancer seen over an 18-year period was carried out at the Department of Clinical Oncology of the University Hospital of Graz. Thirty evaluable cases were analysed. Eight patients had Stage I, 11 had Stage II, 8 had Stage III, and 3 had Stage IV disease. Local control was achieved in the majority, 29/30 (97%), by either surgery alone or combined surgery and radiation therapy. Local recurrence developed in 2 (7%) patients. Further 7 (23%) patients developed distant metastases and were treated in accordance with policies developed for the appropriate stage of the disease in females, with hormonal manipulation for hormone receptor-positive and -unknown patients and chemotherapy for hormone receptor-negative patients. The corrected five-year survival (Kaplan-Meier) is 83% for the entire group, 100% for patients with Stage I disease, 86% in Stage II, and 67% in Stage III and IV disease, respectively. This corresponds well with the results in recently published series. Stage of disease at initial presentation was a significant factor determining survival in our investigation. Our own data as well as recent data from literature suggest that with respect to TNM Stages in mammary carcinoma, there is no prognostic difference between men and women. To what extent improved local control by adequate local therapy or systemic adjuvant treatment modalities may improve overall survival remains to be discussed.

A phase I/II study of 4'-O-tetrahydropyranyl-doxorubicin, 5-fluorouracil, and high-dose leucovorin as first-line therapy in advanced breast cancer patients.

A total of 50 patients were treated weekly with 5-fluorouracil (FU), leucovorin (LV), and 4'-O-tetrahydropyranyl-doxorubicin (THP) as first-line chemotherapy for advanced breast cancer (ABC). In phase I the doses of LV (500 mg/m2, day 1) and FU (350 mg/m2, day 1) were held constant, while the dose of THP (day 1) was escalated, from the initial dose of 10 mg/m2 up to the maximum tolerated dose (MTD). Twenty-eight patients entered phase I, and MTD for THP was defined as 35 mg/m2 in this combination. Dose-limiting toxicities were myelosuppression and hepatotoxicity. In phase II, another 22 patients were treated with THP at a dose level of 30 mg/m2. Including 4 patients already treated at this dose in the first part, 25 patients were evaluable for response: 1 patient obtained a complete response (CR) and 13 showed a partial response (PR), giving an objective response rate of 56%. The median duration of response was 9.1+ months and median survival, 15.5+ months. Side effects were generally mild, with ECOG grade I and II leukopenia in 51% of all cycles and grade III in 3% of the courses. Other toxicity included nausea and vomiting (54% and 8%, respectively) and alopecia (24%), all restricted to ECOG grade I and II. Our results suggest that weekly THP/LV-FU represents an active regimen for first-line treatment of ABC with relative low toxicity.

Weekly 5-fluorouracil and high-dose folinic acid in combination with epidoxorubicin as first-line therapy in advanced breast cancer: a phase II study.

A total of 25 patients with advanced breast cancer were treated weekly with i.v. 5-fluorouracil at 350 mg/m2, folinic acid at 500 mg/m2, and epidoxorubicin at 35 mg/m2 as first-line chemotherapy for a maximum of 18 cycles. In all, 24 patients were evaluable for response. Overall, 1 patient achieved a complete response and 11 patients showed a partial response, for an objective response rate of 50%; the median duration of response was 18.3+ months and median survival amounted to 18.8+ months. Side effects were generally mild, with grade II leukopenia occurring in 10 patients and grade III leukopenia, in 1 patient. Other toxicity included nausea and vomiting (82%), diarrhea (48%), stomatitis (48%), and alopecia (92%), all of which were mainly restricted to WHO grades I and II. Our results suggest that leucovorin modulation of 5-fluorouracil can safely be incorporated into combination chemotherapy with epidoxorubicin on the investigated schedule. The observed response rate appears comparable with that obtained with other first-line regimens.

The presence of immunosuppressive 'p15E-like' factors in the serum and urine of patients suffering from malign and benign breast tumours.

Certain types of tumours are capable of producing factors inhibiting mononuclear phagocyte chemotaxis which may contribute to defects in immunosurveillance. In head and neck cancer these factors are said to be related to the retroviral protein p15E. This study examines the presence of p15E-like factors in serum and urine of patients with malign and benign breast tumours. Thirty patients with breast cancer, 29 patients with benign breast masses, and 28 healthy controls were tested blindly with the monocyte polarization assay, using N-formyl-methionyl-leucylphenylalanine as chemo-attractant. The low molecular weight fractions prepared of sera of the malign tumour patients inhibited the monocyte polarization significantly (mean inhibition 34%, s.d. = 12) compared with those of benign tumour patients (15%, s.d. = 7) and of controls (14%, s.d. = 6). The observed inhibitory effects on the monocyte polarization could be compensated by MoAbs reactive to p15E-related antigens. The mean difference between the polarization inhibition with and without anti-p15E adsorption (the 'p15E-like factor-induced inhibition') was 25% (s.d. = 13) in the breast cancer group, compared with 7% (s.d. = 5) in the benign tumour patients and 5% (s.d. = 4) in the healthy control group. Surgical removal of the tumours resulted in a restoration of the monocyte polarization in 20/23 (87%) patients of the breast cancer group. Results testing preoperative urine samples correlated well with those of corresponding sera. These data give additional support to the concept that tumour-derived p15E-like factors are responsible for the inhibitory effect on monocyte chemotaxis in breast cancer patients, and that these factors can be found in serum as well as in urine.