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Biomedical subjects

S Ferrari

Publications and source records attributed to S Ferrari.

At least 253 records · Page 14Linked to original sources
PubMed1993

Influence of adriamycin dose in the outcome of patients with osteosarcoma treated with multidrug neoadjuvant chemotherapy: results of two sequential studies.

The results of two sequential studies of neoadjuvant chemotherapy for osteosarcoma of the extremities performed at Rizzoli Institute between 1986 and 1991 in 228 patients are presented. In both studies preoperative chemotherapy consisted of two cycles of high dose methotrexate (HDMTX), cisplatinum (CDP) and adriamycin (ADM). Postoperatively the good responder patients were treated with the same drugs used before surgery while in the poor responder patients ifosfamide was added to these three drugs. The preoperative treatment was the same in both studies while after surgery in the second protocol either the cumulative dose of ADM (270 mg/m2 instead of 360 mg/m2) or the single dose per cycle of this drug (60 mg/m2 instead of 90 mg/m2) was reduced. These changes in the last protocol were done to reduce the cardiotoxicity of ADM that was high in the first study (2 deaths and 1 heart transplantation). Since in the last protocol--in comparison with the first protocol--after surgery chemotherapy was restarted earlier and ADM was administered not as a single drug but in combination with the CDP the dose intensity of ADM was unchanged while the dose intensity of MTX, CDP and ifosfamide was higher than in the first study. The preliminary results of the 84 patients treated in the second study show a 2-year disease free survival significantly lower than that achieved in the 144 patients treated in the first study (37/51--73% vs 123/144--85%: P < 0.008). In addition, even if in the last study there were no cases of clinical cardiotoxicity due to ADM, there was a significantly higher percentage of severe myelodepression that led to two deaths for infectious complications. These results suggest that in neoadjuvant treatment of osteosarcoma the total dose of ADM and/or the single dose per cycle of the same drug are an important determinant of outcome and that increasing the dose-intensity of less toxic but less active agents, MTX, CDP and ifosfamide, at the expense of the more active and more toxic agent, ADM, can lead to a poorer outcome without reducing toxicity.

Adolescent↗
PubMed1993

No advantages in the addition of ifosfamide and VP-16 to the standard four-drug regimen in the maintenance phase of neoadjuvant chemotherapy of Ewing's sarcoma of bone: results of two sequential studies.

Between January 1988 and December 1990, 74 patients with localized Ewing's sarcoma of bone were treated with a new protocol that consisted of an initial 6-week period of chemotherapy with vincristine (VCR), adriamycin (ADM) and cyclophosphamide (EDX) followed by local therapy and additional chemotherapy with the same drugs previously indicated plus ifosfamide and VP-16. The rationale for the addition of ifosfamide and VP-16 to the four drugs of the standard chemotherapy of this tumor was that this drug combination was previously very effective in the treatment of metastases from Ewing's sarcoma even in patients who did not respond to cyclophosphamide. As local treatment all patients were offered surgery, when feasible (70 cases). Forty-three patients accepted and 27 refused. These patients, as the 4 patients in whom surgery was not considered feasible, were treated with radiation therapy alone (50-60 Gy). In the remaining patients amputation was performed in 4 cases, rotationplasty in 3 and resection in 36. Where conservative surgery was marginal or intralesional (30 cases), radiotherapy at lower doses (40-45 Gy) was also delivered. At a mean follow-up of 3.5 years (2-7), 43 patients (58%) remained continuously disease-free and 31 relapsed (29 with metastases and 2 with both metastases and local recurrences). These results do not differ from those obtained at our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol in which only VCR, ADM, EDX and dactinomycin (DAC) were used (3-year continuously disease-free survival (CDFS) respectively of 54% and 55%). Despite the fact that these results came from a nonrandomized study, the Authors conclude that the addition of ifosfamide and VP-16 to the four-drug standard regimen did not improve the outcome of the patients with Ewing's sarcoma of bone which remains a lethal disease in about 50% of the cases. These findings stress the need to find more effective chemotherapeutic regimens for the associated treatment of this tumor.

Adolescent↗
PubMed1993

Dialysis treatment using an ethylene vinyl alcohol membrane and no anticoagulation for chronic uremic patients.

Anticoagulation used in hemodialysis treatment brings with it the risk of hemorrhagic complications and the possible consequences associated with chronic heparin administration. These problems have not been satisfactorily addressed to date. This study examined a new dialysis method that does not require the administration of anticoagulants. Dialysis is performed for 3 h with a continuous infusion of 750 ml of physiological saline solution in predilution mode and using filters made of ethylene vinyl alcohol copolymer membranes. Eleven patients with chronic uremia underwent more than 2,000 dialysis treatments performed with 9 episodes of coagulation of the dialyzer or blood tubings (0.43%). An evaluation of individual treatments revealed a high degree of biocompatibility and only a scanty activation of coagulation. Blood depuration efficacy was very good as evaluated from pretreatment and posttreatment routine blood chemistries. The technique described here represents a simple and effective method for performing regular dialysis treatment and does not require anticoagulant therapy.

Adult↗
PubMed1993

Expression of interleukins 1, 3, 6, stem cell factor and their receptors in acute leukemia blast cells and in normal peripheral lymphocytes and monocytes.

Reverse transcriptase-polymerase chain reaction amplification (RT-PCR) and Southern blot analysis were used to evaluate ligand and receptor expression of interleukin 1 alpha (IL-1 alpha), interleukin 3 (IL-3), interleukin 6 (IL-6) and stem cell factor (SCF) in peripheral blood lymphocytes and monocytes and in several acute leukemia blast cell populations. Resting peripheral lymphocytes and monocytes expressed both ligand and receptor of the four cytokines at considerable levels. The leukemic blast cells of the M1-M4 phenotypes are characterized by almost complete lack of expression of IL-1 alpha, IL-3 and IL-6 and the constant and usually high expression of SCF. On the other hand, these myeloid blast cells express generally high levels of the four cytokine receptors. The data suggest that the regulation of the expression of IL-1 alpha, IL-3 and IL-6, at least in our limited number of leukemic cell populations studied, is independent of that of SCF. The results indicate that, at least in most of the leukemic myeloid blasts cells, the expression of SCF and its receptor, the c-kit oncogene, may permit an autocrine regulation of cell cycling.

Acute Disease↗
PubMed1993

Parathyroid hormone-related protein increases cAMP production in mammary epithelial cells.

Parathyroid hormone-related protein (PTHrP) is a major cause of malignant hypercalcemia but has been found in many nontumoral tissues as well. Thus it is produced by the mammary gland during lactation and released into milk. Whether PTHrP directly affects breast tissue is however not known. We investigated the effects of PTHrP on adenosine 3',5'-cyclic monophosphate (cAMP) production in primary cultures of mammary epithelial cells isolated from lactating rats. On the 7th day in culture, synthetic PTHrP-(1-34), recombinant (r) PTHrP-(1-108), and rPTHrP-(1-141) stimulated cAMP production in a concentration-dependent manner. Thus PTHrP-(1-34) induced a 1.92 +/- 0.04-fold stimulation of cAMP production (mean +/- SE, n = 5 separate experiments, P < 0.001). At the time of maximal responsiveness to PTHrP, a significant proportion of the cells was characterized by an elongated shape and a positive immunofluorescent staining for both prekeratin and alpha-smooth muscle actin 1, compatible with a myoepithelial phenotype. It therefore appears that PTHrP can stimulate the production of cAMP in mammary cells, suggesting a possible autocrine/paracrine regulatory function for PTHrP in breast tissue.

Animals↗
PubMed1993

Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities.

PURPOSE: To evaluate more accurately the effectiveness of preoperative chemotherapy in the treatment of patients with Ewing's sarcoma, we studied histopathologically the chemotherapeutic response and correlated it to oncologic outcome. PATIENTS AND METHODS: Between June 1983 and December 1989, 68 patients with nonmetastatic Ewing's sarcoma of the extremities were treated at our institute with preoperative chemotherapy (without radiation therapy) and surgery. The specimens were retrospectively evaluated for areas of viable tumor cells and graded from I to III (macroscopic, microscopic, or no residual disease, respectively) in a blinded fashion. Clinical follow-up data were available on all patients for a mean of 60 months (range, 32 to 111). RESULTS: This histopathologic analysis was strongly correlated with oncologic outcome (P = .004). Patients who demonstrated grade III response (no identifiable viable tumor nodules present) had improved 5-year disease-free survival rates as compared with patients with grade II (microscopic nodes present; P = .023; 90% v 53%) and grade I responses (macroscopic nodules present; P = .0003; 90% v 32%). Patients with grade II necrosis had statistically improved survival rates over those with grade I necrosis (53% v 32%; P = .074). CONCLUSION: This new histopathologic analysis technique for the evaluation of neoadjuvant chemotherapy effectiveness (which does not rely on tumor volume for its assessment) is a valuable prognostic indicator for patients with Ewing's sarcoma treated with surgery. Based on this preliminary report, cases of grade I or II chemotherapeutic tumor response should be considered clinical failures and a different, more aggressive postoperative chemotherapy regimen should be considered.

Adolescent↗
PubMed1993

Overexpression of c-kit in a leukemic cell population carrying a trisomy 4 and its relationship with the proliferative capacity.

The expression of c-kit and its ligand, the stem cell factor (SCF), was studied in five cases of acute myeloid leukemia. One of these had a trisomy of chromosome 4, where the c-kit oncogene is located. In this case, the c-kit oncogene was overexpressed, but matched by a low expression of its ligand, SCF. The molecular evaluation of the growth rate by c-myc and the histone H3 expression indicated that the growth fraction of this cell population was very low. In one of the other leukemic cell populations studied, characterized by a low expression of c-kit and an elevated expression of the SCF, the growth fraction was also very low. Our results suggest that at least for some receptor oncogenes, the simple overexpression cannot be taken as an indication that the oncogene is involved in the deregulation of cell proliferation.

Base Sequence↗
PubMed1993

[The oral strontium load test in the assessment of intestinal calcium absorption].

A close correlation between calcium and strontium intestinal absorption has been described. In this study, a test using Stable Strontium has been assessed in women without abnormal calcium or bone metabolism, with no history of drugs which might affect calcium or bone metabolism. Decreasing values of Strontium intestinal absorption, according to the length of the postmenopausal period, have been observed. Besides, the Stable Strontium Test has been given in postmenopausal women with osteoporotic femur fractures. In comparison with age matched healthy women, this latter group showed a significantly lower Strontium intestinal absorption. Analogous behaviour has been reported for Calcium intestinal absorption.

Administration, Oral↗
PubMed1993

[Osteosarcoma of the extremities metastatic at presentation. Results obtained with primary chemotherapy followed by simultaneous resection of the primary and metastatic lesion].

From September 1986 to September 1990 35 patients affected by osteosarcoma of the extremities with synchronous metastasis were treated with two cycles of high-dose methotrexate IV, cisplatin IA and adriamycin IV followed, in 22, by simultaneous resection of the primary and metastatic tumor. Six patients progressed and were not operated on, 7 patients with complete response of pulmonary nodules underwent surgical resection of the primary lesion. A complete histological examination of the resected specimens was always performed to evaluate the percentage of necrosis produced by chemotherapy on both the primary and metastatic tumor. After surgery the patients received 3 more cycles of the same drugs as used preoperatively plus ifosfamide. The histological response of the primary tumour was "good" (90% or more tumour necrosis) in 8 patients (27%) and "poor" (less than 90% of tumour necrosis) in 21 (73%) while in the 75 metastatic nodules the resulting necrosis was good in 18 (24%) and poor in 57 (74%). A good correlation between the histological response in the primary and metastatic tumour was observed. At an average follow-up of 30 months (R 12-60), 13 patients are alive, 10 disease-free, and 3 with uncontrolled disease. This data suggest that prognosis of osteosarcoma of the extremities with synchronous metastases remains poor even with a very aggressive treatment. Our results also seem to confirm the validity of the present strategy in the treatment of non metastatic osteosarcoma: to introduce new drugs postoperatively in patients poor responder can allows a better treatment of microscopic disease and can improve the prognosis for these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs.

Partial amino acid sequences were obtained from 22 internal tryptic peptides of rat liver p70s6k (M(r) 70,000 ribosomal protein S6 kinase), 3 of which were found to contain phosphorylated residues. To determine whether these sites were associated with p70s6k activation, the kinase was labeled to high specific activity with 32P(i) in Swiss mouse 3T3 cells. By sequential cleavage with CNBr and endoproteinase Lys-C followed by two-dimensional tryptic peptide analysis, it could be shown that all of the sites were located in a small endoproteinase Lys-C peptide of M(r) 2400. Analysis of the p70s6k protein sequence revealed a single candidate that could represent this peptide. Three tryptic peptides derived from the endoproteinase Lys-C fragment were chosen by a newly described computer program as the most likely candidates to contain the in vivo sites of phosphorylation. Synthetic peptides based on these sequences were phosphorylated either chemically or enzymatically and found to comigrate by two-dimensional thin-layer electrophoresis/chromatography with the four major in vivo labeled tryptic phosphopeptides. Three of the phosphorylation sites in these peptides were equivalent to those sequenced in the rat liver p70s6k. In addition, all four sites display the motif Ser/Thr-Pro, typical of cell cycle-regulated sites, and are clustered in a putative autoinhibitory domain of the enzyme.

3T3 Cells↗
PubMed1992

Osteosarcoma of the extremity metastatic at presentation: results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions).

From September 1986 to December 1989, 26 selected patients with high-grade osteosarcoma of the extremities metastatic at presentation were treated with primary chemotherapy (high doses of methotrexate, -cisplatinum and adriamycin) followed by surgery. Twenty-one cases underwent resections of the primary and metastatic tumor at the same time; owing to the disappearance of lung metastases after preoperative chemotherapy in 3 cases, only the primary tumor was operated on. Due to progression of the disease in 2 patients, no surgery was performed. Histologic examination of the resected specimen was performed to evaluate the percentage of necrosis produced by chemotherapy on the primary and metastatic tumor. After surgery, the patients received further chemotherapy with the same drugs used preoperatively plus ifosfamide and VP-16. The histologic response of the primary tumor was good (> 90% tumor necrosis) in 25% of the cases; in the resected metastatic nodules, 23% had good responses. A discrepancy between the histologic response of the primary and secondary tumor was observed in only 15% of the cases. These results seem to confirm the validity of the strategy (widely used today in the neoadjuvant treatment of non-metastatic osteosarcoma) of changing the postoperative treatment when the histologic response of the primary tumor is poor. At an average follow-up of 3.5 years, only 6 patients remained disease-free; 19 patients relapsed and 1 patient died for adriamycin cardiotoxicity. Of the 19 relapsed patients, 16 died and 3 are still alive but with uncontrolled disease. These results are much worse than those obtained in 144 cases of non-metastatic osteosarcoma of the extremities treated in the same period with the same preoperative chemotherapy (77% with good response in the primary tumor and 78% with continuous disease-free survival). The data suggest that a very effective neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremities gives disappointing results in osteosarcoma of the extremities which is metastatic at presentation.

Adolescent↗
PubMed1992

T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis.

T-cell receptor (TCR) beta-chain proteins appear early (approximately 15th week of gestation) during human thymic ontogenesis. These beta-chain proteins, which appear before terminal deoxynucleotidyl transferase (TdT), could be an expression of a fully rearranged (V-D-J), incompletely rearranged (D-J), or germline TCR beta-chain gene. The aims of this study, performed from the 15th week onward, were the following: (1) to investigate whether or not TCR beta gene rearranges at an early stage during human thymic ontogenesis; (2) to investigate whether complete presumptive functional (1.3 kb) TCR beta gene transcript is present at these early stages of development, or if incomplete (1 kb) or germ-line (1.1 kb) transcripts are expressed; (3) to examine the phenotype of TCR beta-chain+ cells with two-color fluorescence using monoclonal antibody (MoAb) beta F1 and MoAbs that recognize CD1, CD2, CD3, CD4, CD8, CD5, and CD7 antigens (rabbit anti-calf TdT antiserum was used to detect TdT); and (4) to demonstrate whether or not beta gene N-diversity regions are detectable as early as the 15th week and whether or not N-nucleotide insertions correlate to TdT expression. Fifteen- to 22-week fetal thymuses and pediatric thymuses were investigated. We demonstrated that TCR beta-chain gene rearranged as early as the 15th week in human thymus and that a complete functional TCR beta gene transcript was expressed at these early stages of human development. No other analyses to date have investigated TCR beta gene expression in early human thymus using molecular biology techniques. No significant differences were detectable between phenotypic analysis of fetal and pediatric samples, except for TdT expression, which appeared after the 20th week. Essentially all mCD3+ (OKT3+) cells were beta-chain+ at the different weeks investigated. A significant percentage of CD1+ cells were beta-chain+, and the percentage increased along with the age of development. After the 20th week, we identified three main populations: TdT+, cCD3+, beta F-(early thymic precursors); TdT+, CD1+, beta F1+ (intermediate maturity cortical thymocytes); and TdT-, mCD3+, beta F1++ (mature medullary thymocytes). Given these values, we may consider beta-chain expression an ordered process. beta gene N-nucleotide insertions were correlated to TdT expression, since N-regions increased considerably after the 20th week. A further increase of N-nucleotide insertions was detected from the 22nd week to the 32nd week.

Age Factors↗
PubMed1992

Abundance of the primary transcript and its processed product of growth-related genes in normal and leukemic cells during proliferation and differentiation.

The relative abundance of primary transcript and mature mRNA of the c-myc, calcyclin, S14 ribosomal protein, and rRNA genes was determined densitometrically after reverse transcriptase-polymerase chain reaction and Northern blotting analysis in resting and mitogen-stimulated lymphocytes, proliferating and terminally differentiated HL-60 cells, and leukemic blast cells. Transcription and processing of c-myc and rRNA gene transcripts increased proportionally after mitogen stimulation, whereas these processes were independent of cell cycling status in the case of the S14 gene. Normal lymphocytes showed an unexpectedly large amount of primary transcript of the calcyclin gene, whereas the corresponding mRNA was undetectable. The abundance of c-myc, calcyclin, and S14 mRNA in terminally differentiated HL-60 cells decreased sharply, compared to their proliferating counterparts. This decrease reflected post-transcriptional modulation, since the abundance of precursor remained essentially unchanged. After HL-60 differentiation, the 32S rRNA levels remained relatively high, whereas the 45S primary transcript almost disappeared. Leukemic blast cells displayed highly variable precursor/mRNA ratios of c-myc, calcyclin, and S14 genes but consistently high ratios of 32S to 45S RNA, suggesting that the cleavage rate of the 32S rRNA was sharply reduced in these cells, resulting in an accumulation of this molecule. These results suggest the importance of efficient processing of primary transcript to generate adequate functional mRNA, thus regulating gene expression. Furthermore, in terminally differentiated cells and leukemic blast cells a stabilization of the primary transcript without efficient processing can be observed. The role of the stabilization of the primary transcript in terminal differentiation is further supported by the results of run-off transcription, indicating a sharp decrease of c-myc and calcyclin transcription rate in retinoic acid/dimethyl sulfoxide-treated HL-60 cells.

Acute Disease↗
PubMed1992

The DNA binding site of HMG1 protein is composed of two similar segments (HMG boxes), both of which have counterparts in other eukaryotic regulatory proteins.

The mammalian nuclear protein HMG1 contains two segments that show a high sequence similarity to each other. Each of the segments, produced separately from the rest of the protein in Escherichia coli, binds to DNA with high specificity: four-way junction DNA of various sequences is bound efficiently, but linear duplex DNA is not. Both isolated segments exists as dimers in solution, as shown by gel filtration and chemical crosslinking experiments. HMG1-like proteins are present in yeast and in protozoa: they consist of a single repetition of a motif extremely similar to the DNA binding segments of HMG1, suggesting that they too might form dimers with structural specificity in DNA binding. Sequences with recognizable similarity to either of the two DNA binding segments of HMG1, called HMG boxes, also occur in a few eukaryotic regulatory proteins. However, these proteins are reported to bind to specific sequences, suggesting that the HMG box of proteins distantly related to HMG1 might differ significantly from the HMG box of HMG1-like proteins.

Amino Acid Sequence↗
PubMed1992

SRY, like HMG1, recognizes sharp angles in DNA.

HMG boxes are DNA binding domains present in chromatin proteins, general transcription factors for nucleolar and mitochondrial RNA polymerases, and gene- and tissue-specific transcriptional regulators. The HMG boxes of HMG1, an abundant component of chromatin, interact specifically with four-way junctions, DNA structures that are cross-shaped and contain angles of approximately 60 and 120 degrees between their arms. We show here also that the HMG box of SRY, the protein that determines the expression of male-specific genes in humans, recognizes four-way junction DNAs irrespective of their sequence. In addition, when SRY binds to linear duplex DNA containing its specific target AACAAAG, it produces a sharp bend. Therefore, the interaction between HMG boxes and DNA appears to be predominantly structure-specific. The production of the recognition of a kink in DNA can serve several distinct functions, such as the repair of DNA lesions, the folding of DNA segments with bound transcriptional factors into productive complexes or the wrapping of DNA in chromatin.

Amino Acid Sequence↗