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Abstract: In the present study, the primary tumor angiogenesis characteristics of 81 stage IV previously untreated breast cancers with synchronous metastasis to different distant sites (10 patients with soft tissue metastases, 31 with bone metastases, and 40 with visceral metastases) were analyzed. The primary intratumor microvessel density was assessed by immunohistochemical assay on paraffin-embedded primary tumor samples, using a monoclonal anti-CD34 antibody. The mean primary intratumor microvessel density (at 400× fields) was 78±39 (SD) microvessels per field. The microvessel density was not significantly related to the main clinical/pathological features of the tumor (age, cytohistological grade, DNA ploidy, diameter, and receptor status). The percentage of tumor cases with high primary intratumor microvessel density (cut-off median value of the series 73±39 microvessels/field) did not significantly differ in patients with bone, soft tissue, or visceral metastatic disease. Aanalysis of clinical outcome showed a significantly shorter time to progression and overall survival for patients with visceral metastases (P<0.001 and P<0.0002 by log-rank, respectively). Presence of visceral metastases was confirmed to be the only independent prognostic factor related to a worse TTP (hazard risk 2.15, 95% confidence interval 1.14–4.03, P<0.02) and overall survival (hazard risk 1.81, 95% confidence interval 0.98–3.35, P<0.06) by multivariate analysis. In conclusion, the assessment of neoangiogenesis of primary breast cancer by CD34 expression does not provide information predictive of different distant sites of metastasis.

In order to verify whether the HER-2/neu gene is involved in the initial phases of neoplastic disease or in its progression, we evaluated the amplification and overexpression of this gene in the primary tumor and in synchronous metastatic axillary lymph nodes of 26 women with operable breast cancer.HER-2/neu was amplified in 35% and overexpressed in 33% of the primary sites; similar percentages were found in lymph nodes. The clear correlation between the two disease sites regarding gene, mRNA and protein levels, supports the hypothesis that this gene is involved in the initial and invasive phases of neoplasia. Its actual role with respect to other biological tumor characteristics during the metastatic process should be investigated further.

In the present study we tested numerous soluble immunological parameters (soluble Interleukin 2 receptor, Beta 2 microglobulin, Neopterin, soluble CD8 antigen, gamma Interferon and alpha Tumor Necrosis Factor) in sera obtained from 18 advanced cancer patients during subcutaneous treatment with recombinant Interleukin 2. The treatment cycles consisted of a dose of 9×106IU/m2twice daily for 2 days followed by 1.8×106IU/m2twice daily for 5 days/week during 6 weeks. Even before therapy, neoplastic patients had higher levels of soluble Interleukin 2 receptor than a group of healthy subjects. Moreover, basal soluble CD8 antigen levels showed significant differences (p<0.01) in patients with different clinical responses (responders and non-responders).During treatment we observed a fast increase (in the first or second week) of all parameters considered; soluble Interleukin 2 receptor and soluble CD8 antigen were the markers that were best related to the course of immunotherapy.In conclusion, monitoring recombinant Interleukin 2 immunotherapy with immunological parameters in serum seems to be of interest. However, more data are necessary to confirm the real value of the single markers.

The expression of glutathione S-transferase mu was measured by a qualitative immunoenzymatic assay in the blood samples of 108 women (63 breast cancer patients and 45 healthy controls) in order to analyze the relationships of GST-mu phenotype and smoking habits with tumor characteristics of breast cancer patients, such as tumor extension, nodal status, hormone receptor status and DNA content by flow cytometry. GST-mu was expressed in 53/108 (49%) of cases without any significant difference between healthy or neoplastic subjects, smokers or non-smokers, pre or post-menopausal, younger or older subjects. Moreover, the percentages of the GST-mu phenotype did not differ significantly in patients with different ER and PgR tumor status, tumor extension or nodal status. By contrast, aneuploid DNA tumor content was shown to be significantly associated with GST-mu expression (24% and 76% GST-mu positive, respectively, in diploid and aneuploid cases; p < 0.003). The biological meaning of this association remains to be interpreted.

The aim of our study was to verify the efficacy and tolerability of subcutaneous low doses of interleukin-2 with cisplatin and dacarbazine for malignant melanoma. 24 patients were included. The following schedule was used: cisplatin (CDDP) 100 mg/m2 day 1; darcarbazine (DTIC) 375 mg/m2 days 1–5; recombinant interleukin-2 (rIL-2) 4.5 million IU × 2/day days 13–17 and 20–24. The therapy was recycled every 28 days. 10 patients obtained clinical remission (42%), with 2 complete responses (8%) persisting for 12 and 15+ months, and 8 partial responses (35.5%) with a median duration of 5 months. Median survival of all 24 patients was 8 months, 13 months for responders and 6 months for non-responders. Responses were seen predominantly in lymph nodes (48%) and skin-soft tissue (38%), but were also seen in the liver (29%) and lung (14%). Treatment was relatively well tolerated and toxicity was mainly related to chemotherapy.

Even though several radiological and laboratory tests are currently used in clinical practice for breast cancer surveillance, the benefits of early detection of distant metastases have never been established. Two recently published randomized clinical trials assessing the effectiveness of an intensive follow-up strategy (with periodic clinical examination, mammography, bone scan, liver echography, chest-X-ray and laboratory tests) over a minimalist one (including only periodic clinical examination and mammography) failed to show a significant advantage for the more intensive policy. Intensive follow-up, however, is quite common in clinical practice.

Summary The relationship between cell kinetics and hormonal status and the relevance of the cell kinetic variable on success of hormonetherapy in estrogen receptor positive (ER+) breast tumors were analyzed in patients with advanced disease. Cell kinetics were evaluated as in vitro3H-thymidine labeling index (LI), and estrogen receptor (ER) and progesterone receptor (PgR) with the dextran-coated charcoal technique. The analyses performed on primary tumor or soft tissue metastases from 52 patients showed a general association between the presence of hormone receptors and low proliferative activity, or the absence of receptors and high proliferative activity (ER and L.I.: p>0.05; PgR and L.I.: p = 0.05). However, hormonal status and cell kinetic status were unrelated in about 40% of the cases. Clinical response to additive hormonotherapy was analyzed in relation to pretreatment LI in 29 patients with ER+ tumors. Time to reach maximum response was significantly longer in slow than in fast proliferating tumors, but complete remission was reached in 88% of slow proliferating tumors compared to only 46% of fast proliferating tumors. These preliminary results show that ER+ fast proliferating tumors largely escape hormonal control, and if confirmed on larger series, could identify cell kinetics as an important tool to select patients who will benefit from hormonal treatment.

Using a new immunoradiometric assay (ELSA pS2 Cis-France), a total of 200 cytosols obtained from primary breast tumors were examined for pS2 content, which is an estrogen-regulated protein actually studied as a marker of hormone sensitivity and favorable prognostic factor in breast cancer. In our patient group, the median pS2 value corresponding to 5.3 ng/mg of cytosolic proteins was used as cutoff. pS2 content was not related to menopause status, tumor size, or nodal involvement, whereas a positive correlation was found between pS2 and ER/PgR status. Moreover, the association of pS2 with steroid receptors seems to identify subgroups of patients better than ER/PgR alone.

A reversed phase high performance liquid chromatographic method has been developed for the simultaneous determination of the pro-drug 5′-deoxy-5-fluorouridine (5′-dFUR), its metabolite 5-fluorouracil (5-FU) and some fluorinated pyrimidines involved in the metabolic activation process of 5-FU. The method has been used to monitor the bioavailability of 5′-dFUR and 5-FU in patients undergoing anticancer chemotherapy. Serum sample treatment involves addition of internal standard (5-bromouracil), protein precipitation with saturated ammonium sulphate solution and liquid-liquid extraction with ethyl acetate-isopropanol (90 ∶ 10 v/v). Urine is simply diluted with mobile phase and injected. The average recovery from serum (at 0.5 μg/mL level) was 95.0%±1.4 for 5′-dFUR and 86.3%±3.5 for 5-FU. A linear response extending over four decades of concentration was observed. Detection limits in the low ng/ mL range were obtained using a 250 μL sample size and a 20 μL injection volume. Within-day and between-day coefficients of variation were below 4 and 10%, respectively.

Gemcitabine, a novel nucleoside analogue, has significant single-agent activity in a number of chemoresistant tumours such as ovary and non-small cell lung cancer. In an early phase I study with gemcitabine (dose: ≥875mg/m2; schedule: wk ×3 q4 wks), 1 complete and 2 partial responses were observed in 14 previously treated metastatic bladder cancer patients (overall response rate 21.4%). We report a phase II study of gemcitabine in patients with stage IV bladder cancer who had been treated unsuccessfully with one previous cisplatin-containing regimen. Characteristics of all 18 patients entered into the study were: 15 males; median age 65.1 years (range 39–75), Karnofsky PS 60 (3 pts), 70 (7), 80 (4), 90 (2), 100 (2). Gemcitabine 1250mg/m2was given once a week for 3 weeks followed by one week of rest (one cycle). Of 14 patients eligible for efficacy analysis (4 patients too early), having received treatment for at least 2 cycles, there were 2 complete responses and 2 partial responses for an overall response rate of 29%. All 18 patients were evaluable for toxicity. There were no WHO grade 3 or 4 non-laboratory toxicities. The only WHO grade 4 laboratory toxicity was thrombocytopenia (1 pt). WHO grade 3 laboratory toxicities were: thrombocytopenia (1 pt), ALT (1), AST (1), creatinine (1), vomiting (2), anaemia (1). This study confirms that gemcitabine has single-agent activity in stage IV bladder cancer and has a mild to modest toxicity profile.