Vascular endothelial growth factor expression, S-phase fraction and thymidylate synthase quantitation in node-positive colon cancer: relationships with tumor recurrence and resistance to adjuvant chemotherapy.

BACKGROUND: The behaviour of colorectal carcinomas may depend on molecular properties of tumors. In node-positive colon cancer, we assessed the S-phase fraction (SPF) index, the vascular endothelial growth factor (VEGF) expression and the TS levels. The combined analysis of SPF/VEGF was studied for predictivity of recurrent disease, the TS quantitation was related to the efficacy of fluorouracil-based adjuvant chemotherapy. PATIENTS AND METHODS: Consecutive patients with surgically-resected, node-positive colon cancer were studied. Flow cytometry for the SPF and immunohistochemistries for the TS and the VEGF expression were carried out on the primary tumor. Recurrences had to be proven by biopsy or surgery, and they were categorized as early, if occurred within 12 months after surgery, or late if occured 13 months or more. RESULTS: Of 150 evaluable patients, 100 had received fluorouracil-based adjuvant chemotherapy and 50 control patients were untreated. The combined analysis of the VEGF and the SPF showed a strong association between the two markers; 48 patients (32%) had high SPF/VEGF positive tumors and 69 patients (46%) had low SPF/VEGF negative tumors (P < 0.0001). The majority of disease-free patients (73.4%) showed VEGF negative/low SPF tumors (P < 0.0001). Early recurrences occurred more frequently in patients with VEGF positive/high SPF tumors (P < 0.001). In the 100 patients treated with adjuvant chemotherapy, 86% of relapsed patients had TS overexpressing tumors and 69% of disease-free patients had TS negative tumors (P < 0.001). Also, early recurrences occurred more frequently in TS overexpressing tumors (P < 0.0001). CONCLUSIONS: Evidence is supported that node-positive colon cancer constitutes a heterogenous disease. Patients with VEGF positive/high SPF tumors showed an unfavourable outcome compared to patients with VEGF negative/low SPF tumors. The efficacy of fluorouracil-based adjuvant chemotherapy may depend on the TS status.

S-phase fraction can predict event free survival in patients with pT2-T3N0M0 colorectal carcinoma: implications for adjuvant chemotherapy.

BACKGROUND: Adjuvant chemotherapy for colorectal carcinoma was found to improve survival of patients with American Joint Committee on Cancer/International Union Against Cancer Stage III disease. The usefulness of chemotherapy in patients with Stage II disease continues to be debated, and it is likely that only those patients with a poor prognosis should receive adjuvant chemotherapy. Biologic prognostic factors may allow further insight into the optimal treatment strategy for patients with Stage II or earlier disease. In this study the prognostic role of S-phase fraction (SPF) determined by flow cytometry was assessed in patients with Stage I-II colorectal carcinoma. METHODS: Specimens of surgically resected colorectal carcinoma were examined for SPF by flow cytometric DNA analysis. Consecutive patients referred to the study institution were considered eligible for this study. The main inclusion criteria were a Stage I-II tumor together with sufficient tumor material and adequate follow-up information. For each stage of disease, SPF data were associated with the recurrence rate and the disease free survival (DFS). RESULTS: Analysis was performed on 167 patients (65 with Stage I disease and 102 with Stage II disease). Among Stage I patients, SPF was high in 20 patients and low in 45 patients. In Stage II patients, there were 36 patients with low SPF and 66 patients with high SPF. In both stages, the recurrence rate and DFS were significantly worse for the subgroups of patients with high SPF. CONCLUSIONS: SPF has revealed prognostic differences among patients with surgically resected Stage I-II colorectal carcinoma. These data should be considered for planning future trials in the adjuvant setting because patients with high SPF may benefit from adjuvant chemotherapy.

Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients.

BACKGROUND & AIMS: Octreotide was shown to inhibit the growth of colon cancer and to reduce serum concentrations of tumor growth factors such as insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) in vitro and in animal models. Effects of octreotide on tumor cell kinetics and serum concentration of IGF-I and EGF in patients with colorectal cancer were evaluated. METHODS: Seventy-five patients with colorectal cancer were randomized to receive octreotide (200 micrograms daily) in the 2 weeks before surgery or the usual medications. Samples of tumor tissue were taken at endoscopy and at surgery. [3H]Thymidine labeling index and flow cytometry were used to assess the S-phase fraction. In octreotide-treated patients, plasma levels of IGF-I, EGF, and growth hormone were assessed before and after treatment. RESULTS: There was a statistically significant reduction in the mean percentage of the S-phase fraction as a result of octreotide treatment measured by both [3H]thymidine labeling index (P = 0.001) and flow cytometry (P = 0.001). No reduction in the percentage of the S-phase fraction was observed in the control group patients. Serum values of IGF-I were significantly reduced by octreotide, whereas EGF and growth hormone levels were not affected. CONCLUSIONS: Octreotide reduces the proliferative activity of tumor cells and the serum IGF-I levels in patients with colorectal cancer. This activity may have a role in the treatment of colorectal cancer.

Measurements of cellular proliferation by H-3-thymidine-labeling index and flow cytometry in breast cancer patients.

In 50 node negative breast cancer patients, tumor S-phase fraction (SPF) was determined by H-3-thymidine labeling index ((HTLI)-H-3) or flow cytometry (FC). Forty-five patients had tumor cell kinetics measured by both techniques. Twenty-three patients were classified as having high proliferative activity and 22 low by (HTLI)-H-3, while 32 as highly proliferating and 13 low proliferating by FC. In 30 patients only, both indices agreed on identifying high or low proliferative activity. These results suggest the need of more careful attention to standardization and quality control of cell kinetic data before carrying out clinical trials based on these parameters.

S-phase fraction and tumor aneuploidy in colorectal carcinoma of young patients.

BACKGROUND: Young patients with colorectal carcinomas are considered to have a worse prognosis than older patients. It was the goal of this study to assess if biologic characteristics of tumors in young patients differ from those observed in 2 different groups of patients with the same clinical characteristics but ranging in age either from 41 to 60 years or 61 years and older, respectively. METHODS: Colorectal carcinoma tumor samples were obtained from storage from patients age 40 years and younger and examined for tumor ploidy and S-phase fraction. For each younger patient, a control was selected among patients matched for Dukes stage, site of primary tumor, and sex, with the two age groups. RESULTS: Thirty-one of 1361 patients (2.2%) with colorectal carcinoma treated at our institution between 1984 and 1994 age 40 years or younger. Tumor aneuploidy was present in 3 younger patients, in 5 patients in the 41 to 60 years age group, and in 5 patients in the 61 years and older age group. S-phase fraction was 27.67 +/- 13.62 in patients younger than 40 years, 25.35 +/- 11.6 in the 40 to 61 years age group, and 22.45 +/- 8.48 in the 61 years and older age group. These differences were not statistically significant. CONCLUSIONS: It appears that there are no significant differences in S-phase fraction and tumor aneuploidy in patients younger or older than 40 years, suggesting that colorectal tumors arising in young people do not have different biologic properties.

Oral escalating dose of cyclosporine-a combined with 4-epidoxorubicin in advanced colorectal-cancer - a phase-I study.

Multidrug resistance, a major factor in the resistance to drugs, can be reversed by cyclosporin A. It is generally given by intravenous route. The aim of the present study was to assess the possibility of achieving useful plasma levels, giving cyclosporin A orally in advanced colorectal cancer patients treated with 4-epidoxorubicin. Cyclosporin A was given orally twice a day, for four days. The starting study dose was 5 mg/kg. Dose in cohorts of 3 patients was escalated to 10, 15, 20, 30, 40 mg/kg if the previous dose was not able to determine the target blood level (2,000 ng/ml). Cyclosporin A blood levels were analyzed by a specific fluorescence polarization immunoassay method (TDx; Abbot Laboratoires, North Chigaco, IL). 4-epidoxorubicin was given at a fixed dose of 75 mg/m(2), every 3 weeks. None of the dose levels of cyclosporin A given orally produced the target blood level. Only two patients, receiving cyclosporin at a dose of 30 mg/kg, and two after a CsA dose of 40 mg/kg, presented blood levels higher than 1,000 ng/ml, but however, lower than 1,500 ng/ml. In conclusion, the oral route of administration of cyclosporin does not seem recommendable in order to reverse multidrug resistance because it is not able to produce sufficient plasma levels.

Correlation among [h-3] thymidine, flow-cytometry and proliferating cell nuclear antigen indexes in colorectal tumors.

In colorectal cancer and other tumors, proliferating cell nuclear antigen (PCNA) has been found to be a useful marker in immunohistochemical studies of cell proliferation, The presence of a correlation among PCNA labeling index (PCNA LI) and values of cell proliferation expressed by [H-3]thymidine labeling index (TLI) and flow cytometry (FC), the most common techniques used in the evaluation of proliferative activity in colorectal cancer were studied. In 50 operable colorectal cancer patients, TLI, PCNA LI and determination of S-phase fraction by FC were carried out in order to evaluate the correlation among these three indices. A good correlation was obtained between PCNA LI and both TLI (r=0.667; P=0.0001) and percent of cells in S-phase as determined by FC (r=0.819; P=0.0001). It is concluded that PCNA immunohistochemistry can be a reliable marker of the proliferative activity in colorectal rumours. Furthermore, because of its technical simplicity and lower cost it can be more advantageous than TLI or FC.

Cytokinetic effects of interferon in colorectal cancer tumors: implications in the design of the interferon/5-fluorouracil combinations.

Interferon (IFN) has been shown to enhance the cytotoxic effects of 5-fluorouracil (5FUra) in colorectal cancer, and clinical trials with this combination resulted in higher response rate with respect to 5FUra alone. IFN is generally administered s.c. three times a week. This prolonged exposure could determine a block of tumor cells in the G0-G1 phase of the cell cycle, thus rendering tumor cells insensitive to 5FUra, an S-phase specific agent. In order to verify the presence of this block, 21 operable colorectal cancer patients were treated with IFN-alpha 2b at the dose of 3 megaunits every other day in the week before operation, while another 22 represented the control group. Samples of tumor tissue were taken at endoscopy and operation. [3H]Thymidine labeling index and flow cytometry were used to assess the S-phase fraction. In IFN treated patients, we found a significant statistical difference between the mean percentage of S-phase fractions evaluated either by labeling index (P = 0.00001) or by flow cytometry (P < 0.001). On the contrary, this difference was not present in the control group: labeling index, P = 0.06; flow cytometry, P = 0.08. Furthermore a significant increase in the G0-G1 phase of the cell cycle was found after IFN administration (P < 0.001) but not in the control group. Our results suggest that IFN reduces the S-phase fraction in colorectal cancer tumors. This action should be considered in the design of the 5FUra/IFN combination because it could decrease 5FUra activity, leading to a loss or a decrease in the advantage of 5FUra modulation by IFN.

[Statistic relation between seropositivity to Toxoplasma gondii and several risk factors in a sample of pregnant women]. / Relazione statistica tra sieropositività a Toxoplasma gondii ed alcuni fattori di rischio in un campione di donne gravide.

We analysed, in the period 1984-1986, the serum of 1733 pregnant women. The relation between the positivities and some probable factors of risk, alimentary habits and touch with tame animals has had valued by statistical method. The analysis shows no increase of risk in the group used to eat underdone meats compared with the group in touch tame animals.

Inflammatory malignant fibrous histiocytoma of the kidney: an immunohistochemical and ultrastructural study.

A primary inflammatory malignant fibrous histiocytoma of the kidney is reported. The differential diagnosis from other sarcomas and pseudosarcomatous lesions is discussed on the grounds of the histologic, immunohistochemical and ultrastructural results. The neoplasm was made up of histiocytes, fibroblasts, myofibroblasts, foam cells and undifferentiated mesenchymal cells with admixed granulocytes, lymphocytes and plasma cells. The immunohistochemical study showed a positivity for alpha-1-antichymotrypsin and a weak positivity for alpha-1-antitrypsin in mononuclear and pleomorphic multinucleated tumor cells. PAS-positive, diastase-resistant intracytoplasmic hyaline globules in necrotic cells, examined by electron microscopy, most likely represent lysosomal structures, in accordance with the theories of De Duve, Vattiaux and Von Ardenne.

Fetal liver transplantation in the mini-pig.

After the characterisation of the hematological and immunological status of the mini-pig fetus at different gestational ages of development was performed, two different groups of animals receiving 800 rads of TBI given by a radioactive cobalt source at a dose/rate of 5/6 rad/min or 750 rads of TBI given by a Linear Accelerator at a dose/rate of 25/26 rad/min, both in a single dose exposure, were transplanted with a pool of allogeneic fetal liver cells whose age ranged between 55 and 75 days of gestation. In the first group 1 animal out of 6 is alive and well 30 months post-transplant. In the second group one of the nine transplanted animals survived 78 days. Engraftment was proved by the presence of the donor chromosome in the proliferating bone marrow cells in one animal.

Tracheal Hodgkin's disease. Report of a case.

A tracheal localization of a Hodgkin's disease is described in a 28-year-old man. The diagnosis was made on a tissue fragment spontaneously emitted and was confirmed by a tracheoscopic biopsy. Radiologic examination revealed adenopathy of the anterosuperior mediastinum, but no other localization. It was not possible to determine whether the tracheal localization was initial or consequent to the mediastinal one. However, Hodgkin's lymphomas of this site have not been previously described.

Histomorphologic study of bone marrow in acute leukemia following chemotherapy and autologous bone marrow transplantation.

Twenty-six patients with acute myeloid leukemia, acute lymphoid leukemia and chronic granulocytic leukemia in blast crisis were studied by means of multiple biopsies during a polychemotherapeutic or autologous bone marrow transplant protocol. Following chemotherapy, 3 main phases were observed: leukemic cellular depletion, stromal bone marrow reconstruction, and bone marrow hemopoietic restoration. Following intensive chemotherapy (in 2 patients after cyclophosphamide and total body irradiation) and autologous bone marrow transplantation, the 3 phases appeared to be shorter. A focal or diffuse increase in marrow fibrosis was a common finding in leukemia. An effective antileukemic therapy resulted in a decrease in fibrosis, whereas in some cases a further increase was a precocious sign of leukemia relapse.