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Biomedical subjects

G Scambia

Publications and source records attributed to G Scambia.

At least 163 records · Page 9Linked to original sources
PubMed1997

Prognostic significance of ras/p21 alterations in human ovarian cancer.

Ras/p21 oncoprotein expression and K-ras mutations were analysed by Western blot and/or K-ras oligonucleotide hybridization in 78 primary ovarian cancers, 20 omental metastases, two low malignant potential tumours (LMP), nine benign ovarian tumours and 10 normal ovaries. A cut-off value of an integral of absorbance (i.a.) of 2.20, obtained by receiver operating characteristic (ROC) curve, was shown to be the best cut-off for defining p21 positivity. p21 levels were higher in malignant tumours than in benign tumours (median 2.10 i.a. vs median 1.22 i.a.; P = 0.014) and in omental metastases than in primary ovarian carcinomas (median 2.54 i.a. vs median 2.1 i.a.; P = 0.0089). p21 overexpression did not correlate with any of the clinicopathological parameters examined. Follow-up data were available for 63 patients. A significant relationship was shown between p21 positivity and a shorter overall survival (OS) (P < 0.03) and progression-free survival (PFS) (P < 0.03). In multivariate analysis only the presence of ascites, p21 levels and epidermal growth factor receptor status retained an independent prognostic role. K-ras gene mutations were frequently detected in benign and low malignant potential tumours (71.4%), which were mostly mucinous (P = 0.0152).

Animals↗
PubMed1997

Relationship between cathepsin-D content and disease-free survival in node-negative breast cancer patients: a meta-analysis.

Several reports have evaluated the correlation between cathepsin-D and overall survival or disease-free survival in node-negative breast cancer patients. Because conflicting data have so far been reported, a meta-analysis was conducted to clarify this problem. Eleven studies were included in our meta-analysis (total of 2690 patients). A specific meta-analytical methodology for censored data was used, and disease-free survival was the primary end point. Patients with low cathepsin-D levels had a significantly better disease-free survival than patients with high cathepsin-D values (meta-analytical odds ratio from 0.59 to 0.60 over the interval from 1 to 7 years). A secondary meta-analysis conducted exclusively on the data from eight studies based on cytosol assay gave substantially similar results. One limitation of our study is that the cut-off values to define high and low cathepsin-D concentrations were not identical in the various studies included in our meta-analysis (range from 20 to 78 pmol mg(-1) protein), thus introducing a possible bias in the statistical analysis of the data. However, a simulation based on the well-accepted method of the so-called publication bias showed that more than 100 null studies would be required to lead our results to a statistical level of non-significance. Considering the results of our meta-analysis, we conclude that the data presently available confirm a statistically significant association between high cathepsin-D values and poor disease-free survival in node-negative breast cancer patients.

Breast Neoplasms↗
PubMed1997

Generation of multinuclear tartrate-resistant acid phosphatase positive osteoclasts in liquid culture of purified human peripheral blood CD34+ progenitors.

Circulating CD34+ cells were isolated from leukapheresis products collected from patients with ovarian cancer. CD34 contaminating cells, identified immediately after immunoselection, ranged from 5% to 25% in five different experiments and were predominantly CD3+ T-lymphocytes (range 2-12%), CD3+/CD16+/CD56+ natural killer cells (range 2-11%) and rare mature CD15+/ CD11b+ granulocytes (range 1-2%). CD34+ cells were cultured in liquid medium in the presence of interleukin-3, granulocyte-macrophage colony stimulating factor. stem cell factor, granulocyte colony stimulating factor and a powerful proliferation with prevalent differentiation along the granulocytic/monocytic lineage was obtained. After 10 d of culture a small but consistent number of early multinucleated osteoclasts were identified with a frequency of one cell per 700 granulocytic/monocytic cells, as revealed by cytologic examination. This observation was confirmed by staining for tartrate-resistant acid phosphatase activity which revealed red multinucleated elements with a frequency comparable to that reported above. Conversely, no osteoclasts were observed in those cultures in which macrophage overgrowth was obtained by culturing CD34+ cells until day 35. These observations suggest that circulating progenitors have a multilineage potential in vitro and contribute to the clarification of osteoclast development in humans: additionally, they provide the basis for the future development of optimized osteoclast culture techniques in liquid medium and the basic culture system, to test the distinct activity of 1,25(OH)2D3. parathyroid hormone interleukin-11 and of other cytokines on osteoclast development in humans.

Acid Phosphatase↗
PubMed1997

Purified unfractionated G-CSF/chemotherapy mobilized CD34+ peripheral blood progenitors and not bone marrow CD34+ progenitors undergo selective erythroid differentiation in liquid culture in the presence of erythropoietin and stem cell factor.

A combination of erythropoietin (EPO) plus stem cell factor (SCF) drove purified unfractionated granulocyte colony stimulating factor (G-CSF)/chemotherapy mobilized peripheral blood CD34+ cells to selective erythroid differentiation in liquid culture with an average 28-fold increase in the total cell number after 21 d. From day 6 of culture cytologic and cytofluorimetric characterization revealed that cultured cells belonged to the erythroid lineage with a gradual wave of maturation along the erythroid pathway to terminal cells. A similar pattern of erythroid differentiation was observed when the same peripheral blood CD34+ cells were culture with EPO plus SCF in serum-free medium. This cytokine combination produced selective erythroid differentiation with the complete exhaustion of the clonogenic potential on day 21. In parallel experiments the same circulating CD34+ cells underwent granulocytic/ monocytic differentiation in liquid culture in response to granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and SCF, demonstrating that these CD34+ progenitors had intact pluripotent differentiating potential. Conversely, bone marrow CD34+ cells isolated from bone marrow allografts were unable to selectively differentiate along the erythroid pathway when they were exposed to EPO plus SCF combination. However, these cells maintained a greater number of colony forming cells on day 21 of culture compared to mobilized peripheral blood CD34+ cells. This model is a simple and reliable way to obtain selective erythroid differentiation of peripheral blood G-CSF/ chemotherapy mobilized CD34+ progenitor cells in liquid culture. The absence of cytokines such as GM-CSF and IL-3 in the culture medium permits studies on in vitro erythropoiesis without disturbance of prevalent myelopoiesis.

Antigens, CD34↗
PubMed1997

Autologous stem cell transplantation: evaluation of erythropoietic reconstitution by highly fluorescent reticulocyte counts, erythropoietin, soluble transferrin receptors, ferritin, TIBC and iron dosages.

The plasma concentrations of erythropoietin (Ep), soluble transferrin receptors (sTfRs), iron, total iron binding capacity (TIBC) and ferritin were monitored in five leukaemia patients undergoing autologous bone marrow stem cell transplantation (BMSCT) and in 10 lymphoma and 21 ovarian cancer patients undergoing autologous peripheral blood SCT (PBSCT); 9/21 ovarian cancer patients received recombinant human G-CSF and Ep and six recombinant human GM-CSF and Ep following SCT. All parameters were evaluated in relation to the kinetics of erythroid reconstitution as evaluated by haemoglobin (Hb) and reticulocyte levels [including the fraction of immature reticulocytes, also called highly fluorescent reticulocytes (HFR)]. Leukaemia patients undergoing BMSCT showed only a delayed (occurring at days 35-50 after SCT) and partial RBC, neutrophil and platelet recovery, whereas all patients undergoing PBSCT exhibited a rapid (occurring at days 10-15 after SCT) and sustained haemopoietic recovery. The various levels of erythroid rescue observed among these patients markedly influenced the kinetics of the different parameters investigated: (i) in leukaemia BMSCT patients sTfRs declined following SCT and remained at low levels thereafter, whereas Ep, iron. TIBC and ferritin showed a progressive and significant increase; (ii) in the different groups of patients undergoing PBSCT: (a) sTfR levels first declined following SCT and then returned to pre-therapy values at days 12-16, this response preceded erythropoietic recovery; (b) Ep, total iron, TIBC and ferritin showed an initial increase in the first days following SCT and then returned to pre-therapy values. Altogether, these observations indicate that: (i) both sTfR levels and reticulocyte counts are predictive parameters of erythropoietic recovery; (ii) coordinated changes of biochemical parameters underlying iron metabolism (iron, TIBC and ferritin) accompany erythroid rescue following SCT.

Adolescent↗
PubMed1997

Evaluation of two different protocols for peripheral blood stem cell collection with the Fresenius AS 104 blood cell separator.

OBJECTIVES: Reconstitution of hematopoiesis by means of peripheral blood stem cells is a valid alternative to autologous bone marrow transplantation. The aim of this investigation was to increase the efficiency of collection of circulating blood progenitor cells and to obtain a purer product for transplant. METHODS: We carried out leukapheresis procedures with the Fresenius AS 104 blood cell separator, using two different protocols, the previously used PBSC-LYM and a new mononuclear cell collection program. RESULTS: Both programs were highly effective in collecting mononuclear cells (MNC) and CD34+ cells. Some differences were found, especially regarding MNC yield and efficiencies. There are remarkable differences in the efficiency of collection of CD34+ cells (62.38% with the new program as opposed to 31.69% with the older one). Linear regression analysis showed a negative correlation between blood volume processed and MNC efficiency only for the PBSC-LYM program. Differences were also observed in the degree of inverse correlation existing in both programs between patients' white blood cell precount and MNC collection efficiency. The inverse correlation was stronger for the PBSC-LYM program. Seven patients with solid tumors and hematologic malignancies received high dose chemotherapy and were subsequently transplanted with peripheral blood stem cells collected using the new protocol. All patients obtained a complete and stable engraftment with the reinfusion product collected with one or two leukapheresis procedures. CONCLUSIONS: High efficiencies and yields were observed in the new protocol for MNC and CD34+ cells. These were able to effect rapid and complete bone marrow recovery after myeloablative chemotherapy.

Adolescent↗
PubMed1997

Growth factor administration following autologous peripheral blood progenitor cell transplantation.

Hematopoietic growth factor (HGF) administration following autologous peripheral blood progenitor cell transplantation (APBPCT) is a current approach for shortening the duration of high-dose chemotherapy-induced transient peripheral pancytopenia. Several published clinical experiences and a retrospective study reported here show that recombinant human granulocyte colony stimulating factor (rhG-CSF) or recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) administration potentiates polymorphonuclear leukocyte (PMN) and white blood cell (WBC) recovery with some clinical benefits mainly related to the reduction of infectious complications during the shortened period of neutropenia. However, this therapeutic strategy does not produce any enhancement of platelet (PLT) recovery or potentiation of red cell production. Conversely, a recent phase I/II study carried out in our institution showed that the combined administration of rhG-CSF and recombinant human erythropoietin (rhEPO) is able to potentiate trilineage hematopoietic recovery with a reduction of PLT transfusions and to considerably simplify the clinical management of patients as compared to patients treated with APBPCT alone. The post-APBPCT administration of rhEPO with rhGM-CSF decreased the number of days with WBC < 1 x 10(9)/L but failed to produce any appreciable effect on PLT recovery. Both combined treatments significantly reduced the patients' hospital stay and allowed the abrogation of systemic antibiotic administration following APBPCT. A further group of patients were treated with the combined administration of rhEPO, rhG-CSF and rhGM-CSF; they did not show a faster hematopoietic recovery than rhG-CSF plus EPO treated patients and a consistent hyperthermia was observed in most patients as a prominent side effect. Future prospective randomized studies will clarify the efficacy of HGF administration following APBPCT. Moreover, further improvements in the hematopoietic support of transplanted patients may be obtained when stem cell factor, flt3/flk2 tyrosine kinase ligands or megakaryocyte growth and development factor will become clinically available.

Erythropoietin↗
PubMed1996

Modified type IV-V radical hysterectomy with systematic pelvic and aortic lymphadenectomy in the treatment of patients with stage III cervical carcinoma. Feasibility, technique, and clinical results.

BACKGROUND: Due to the high prevalence of perioperative major morbidity and the difficulties in achieving surgical disease free margins, surgery has had no role in the treatment of patients with Stage III cervical carcinoma. METHODS: Forty-two women with International Federation of Gynecology and Obstetrics (FIGO) Stage III cervical carcinoma responding to platinum-based neoadjuvant chemotherapy underwent the maximum surgical effort, comprised of a modified type IV-V radical hysterectomy (37 patients) or anterior pelvectomy (5 patients) with systematic pelvic and aortic lymphadenectomy. Feasibility, modifications of surgical technique, and pathologic and clinical data were analyzed. RESULTS: Surgery was feasible in all 42 patients intraoperatively selected. Disease free margins were achieved in all but one patient. The median operating time was 390 minutes, and the median estimated blood loss was 800 mL. In the last series of patients, these figures declined to 320 minutes and 600 mL, respectively. Major morbidity consisted of severe intraoperative hemorrhage in two patients, pulmonary embolism in four, ureteral fistula in three, and laparocele in three. The number of lymph nodes removed ranged from 30 to 117 with a median of 56. The mean lengths of vagina and lateral parametrium resected were 55 and 48 mm, respectively. Despite perioperative chemotherapy, lymph node metastasis was present in 36% of patients, parametrial disease in 38%, and vaginal disease in 45%. After a median follow-up of 53 months, the 5-year overall and disease-free survival rates of radically operated patients were 70% and 58%, respectively. CONCLUSIONS: Thanks to improved surgical technique and perioperative care, extended radical surgery appears to be feasible with acceptable morbidity in chemosensitive women with Stage III cervical carcinoma and may constitute a valid alternative to radiotherapy in these patients.

Adenocarcinoma↗
PubMed1996

Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism.

We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department.

Antineoplastic Agents↗
PubMed1996

Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF-7 human breast-cancer cells.

In this study the ability of the new pure anti-estrogen ICI 182,780 to modulate the cytotoxic action of adriamycin (ADR) on parental and ADR-resistant MCF-7 (MCF-7 ADRr) human breast-cancer cells was investigated and compared with that of tamoxifen (TAM). TAM enhanced ADR cytotoxicity in MCF-7 ADRr cells in a dose-related manner, but this effect was slight or absent in MCF-7 WT. In contrast, ICI 182,780 was able to enhance ADR toxicity both in MCF-7 ADRr and in the parental cell line. ICI 182,780 was up to 2.5-fold more effective than TAM in reducing the IC50 of ADR in MCF-7 ADRr cells. Analysis of the data by the isobole method showed that the combination ADR/TAM and ADR/ICI 182,780 produced synergistic anti-proliferative activity in MCF-7 ADRr cells. Because ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of anti-estrogens on Pgp expression and activity. Both ICI 182,780 and TAM failed to modulate Pgp expression as assessed by flow cytometry and Western-blot analysis, performed using the monoclonal antibodies MM4.17 and C 219, which are specific for an external or an internal determinant respectively. Pgp activity was investigated by flow cytometry measuring the extrusion of ADR and the cationic dye Rhodamine 123 (Rh 123). ICI 182,780, but not TAM, reduced the activity of Pgp in MCF-7 ADRr cells. Flow cytometry was also used to investigate cell-cycle modifications induced by ADR in MCF-7 ADRr cells, both in the presence and in the absence of anti-estrogens. After 72 hr, higher doses induced an arrest of cells at the G2/M phase. The same effect was visible when lower doses of ADR were combined with ICI 182,780 or TAM. In terms of cell-cycle-blocking activity ICI 182,780 was largely more effective than TAM.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Cathepsin D concentration in primary laryngeal cancer: correlation with clinico-pathological parameters, EGFR status and prognosis.

Sixty-three patients with primary laryngeal squamous-cell carcinoma were followed up for a median of 33 months after surgery. Cathepsin D (Cath D) concentration was assayed using a solid phase 2-site immunoradiometric assay in which the first monoclonal antibody (MAb) was coated on the ELISA solid phase and the second one, MIG8 radiolabeled with 1125-EGF, was used as the tracer. The median value of Cath D (13.8 pM/mg protein) was chosen as cut-off. Cath D > or = median value was closely related to neck lymph node involvement at presentation and to a short metastasis-free survival (MFS) and actual overall survival (OS). The 5-year MFS was 71% for patients with Cath D < median value tumors as compared with 0% for patients with Cath D > or = median value tumors. Lymph node status at presentation was not related to a short MFS and OS. Cox's univariate regression analysis using Cath D as a continuous variable showed that Cath D levels are correlated with neck lymph node metastasis. On multivariate analysis, Cath D status proved to be an independent factor for predicting a short MFS. Cath D assay may prove to be particularly useful in identifying laryngeal cancer patients who, with or without neck lymph node involvement at presentation, are at high risk of metastatic disease and poor outcome.

Carcinoma, Squamous Cell↗
PubMed1996

Locally advanced cervical adenocarcinoma: is there a place for chemo-surgical treatment?

The increased frequency and poor prognosis of cervical adenocarcinoma call for new therapeutic strategies, especially in locally advanced disease. Combined neoadjuvant chemotherapy (NACT)-radical surgery (RS) has been investigated to assess its feasibility and the possible impact on disease outcome. Data were pooled from three consecutive trials on a total of 42 patients with FIGO Stage IB-IIA >4 cm (9), IIB (19), and IIIB (14) cervical adenocarcinomas. NACT regimens consisted of cisplatin (P), bleomycin (B) and methotrexate, high-dose PB, and P and doxorubicin combinations for one to three cycles. Responding patients underwent RS while those still ineligible for RS underwent radiotherapy. Fisher and chi squared tests were used to detect significant factors affecting response to NACT. Cox multivariate regression analysis was used to evaluate parameters affecting response and survival. Medians and life tables were computed by the method of Kaplan and Meier. Median follow-up times were 56 (17-95) and 54 months (15-92) from enrollment and RS, respectively. NACT-induced toxicity was generally mild and did not compromise RS when indicated. The 33 (79%) responders underwent laparotomy, while the 9 nonresponders received radiotherapy. RS was feasible in 29 (69%) patients. Macroscopic intraperitoneal tumor (IPT) excluded abandoning RS in 4 cases. Mild to moderate RS-related complications were seen in 41% of cases with the same pattern as in the absence of any prior treatment. In patients undergoing RS, node metastasis and microscopic IPT were detected in 2 (7%) and 3 (10%) patients, respectively. The 5-year overall and disease-free survivals were 71% (100% IB-IIA and 84% IIB vs 36% IIIB; P = 0.001) and 88%, respectively. None of the nonresponders survived (median 10 months, 6-25), compared with an 84% 5-year survival of responders (P < 0.001). FIGO stage and parametrial involvement significantly predicted response to NACT which was the only independent variable affecting survival (P = 0.006). This retrospective study provided evidence of the chemosensitivity of locally advanced cervical adenocarcinoma and that chemoresponsiveness is the most potent predictor of cure, as demonstrated in squamous cell cervical cancer. Combined NACT and RS is a feasible treatment which seems to be able to improve the outcome of Stage IB-IIB cervical adenocarcinoma. Randomized trials comparing this new strategy with conventional treatments seem to be warranted.

Adult↗