Biomedical subjects

S De Santis

Publications and source records attributed to S De Santis.

At least 19 recordsLinked to original sources

PubMed2006

Locally advanced non-small cell lung cancer: role of induction chemotherapy in resectable N2 disease.

Patients with resectable stage IIIA-N2 non-small cell lung cancer should receive induction chemotherapy before surgery. The aim is to early control systemic disease, eventually cure the mediastinal tumor spread and improve patients' survival. A recent metanalysis of randomized trials with second-generation platinum-based combinations has reinforced the evidence concerning the benefit of induction chemotherapy followed by surgery versus surgery alone in resectable disease. Moreover a large number of phase II trials have explored the activity and feasibility of platinum-based combinations with third-generation drugs in the same setting. Still opened questions to address with current clinical research are the eventual role of radiotherapy as induction treatment, the impact of definite chemoradiation versus induction treatment followed by surgical resection on local control and survival and finally the non-easy choice between neo-adjuvant and adjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Second-line chemotherapy for non-small cell lung cancer.

Despite being considered a standard of care, administration of second-line chemotherapy for non-small cell lung cancer is limited to patients in good performance status (ECOG PS 0-1) and to selected patients with PS 2. Drugs currently approved by FDA in this setting are docetaxel, gefitinib, erlotinib and pemetrexed, while in Europe those registered with this indication are only docetaxel and pemetrexed. This short review will focus on the role of pemetrexed, from the controlled phase II trial, to the development of the vitamin supplementation strategy to decrease toxicity, to the large phase III registration trial undertaken vs. the standard docetaxel. Moreover, the huge patient material collected during this latter trial has lead to further analyses to clarify several aspects of second-line treatment, from toxicity to quality of life assessment, to its role in elderly patients and to the direct translation in terms of costs. Finally, we will give a brief overview on current trials, that mainly explore the possibility to raise pemetrexed dose, and thus to increase its activity while maintaining an acceptable toxicity.

Antineoplastic Agents↗

PubMed2005

Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy.

BACKGROUND: Elderly cancer patients are often excluded from clinical trials and no data are available on the impact of chemotherapy-related anemia on their functional status and cognitive functions. This observational study investigates the association between hemoglobin (Hb) level and comprehensive geriatric assessment (CGA) variables (MMSE, ADL/IADL, GDS, CIRS and VAS). PATIENTS AND METHODS: We enrolled 42 consecutive lung cancer elderly patients undergoing chemotherapy that were evaluated at baseline and after each CT cycle at least until cycle 2. Hb association with CGA indexes was expressed using Spearman's non-parametric coefficient r. RESULTS: Higher Hb values were significantly associated with more favourable values of all indexes measuring mental and functional capacity, depression and comorbidities. For all indexes except IADL, improvements from baseline were significantly related with concomitant Hb increases. In 14 patients given erythropoietin during the first two cycles, mean Hb increased from 9.2 to 10.8 g/dl, and the mean values of all CGA indexes were improved. On the contrary, in 18 patients not given erythropoietin, Hb varied from 13.0 to 11.2 g/dl and a parallel worsening in all CGA indexes was observed. CONCLUSIONS: Chemotherapy-related anemia is associated with impairment of functional status and cognitive functions. In elderly cancer patients anemia correction or maintenance could be useful to preserve functional independency and protect from mental decay. However, the study results need to be confirmed on a larger series of patients within a controlled clinical trial.

Aged↗

PubMed2003

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease.

In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARalpha prior and after transplant. Median age was 31 years (range 3-50 years). At 10 years, the actuarial probabilities of nonrelapse mortality, relapse and disease-free survival were 32% (95% CI: 8-56%), 33% (95% CI: 6-60%) and 46% (95% CI: 22-70%). Six patients tested PCR +ve (1st HCR n=2; 2nd HCR n=3; 3rd HCR n=1) and 11 PCR -ve (2nd HCR n=11) pre-SCT. Of the six patients PCR +ve, two showed early persistence of PCR positivity and converted to sustained PCR negativity after CSA withdrawal (one died of secondary tumor in molecular remission and one is alive in relapse), while four converted to PCR -ve rapidly (one died of the underlying disease and three are in molecular remission). Of the 11 patients PCR -ve pre-SCT, six died (four of transplant-related mortality, one of relapse and one after heart transplantation) and five are alive, four in molecular remission and one is in relapse. Allogeneic SCT seems a valid option for advanced APL, particularly for the poor prognostic group of patients with pre-SCT molecularly persistent disease.

Adolescent↗

PubMed2002

Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.

Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.

Acute Disease↗

PubMed2001

Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676).

We report a patient with acute promyelocytic leukaemia (APL) who received two doses of gemtuzumab ozogamicin for advanced disease. Previous treatments included front-line all-trans retinoic acid and anthracyclines, polychemotherapy consolidation, salvage chemotherapy for the first relapse followed by autologous stem cell transplantation (ASCT), arsenic trioxide for the second relapse followed by a second ASCT and then high-dose methotrexate for more advanced systemic disease with central nervous system involvement. The patient achieved prolonged haematological and molecular remission after monotherapy with gemtuzumab ozogamicin given at the time of the third relapse.

Adult↗

PubMed2000

Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis.

In this study we investigate the neurotoxic action of Cisplatin (6 micrograms/g body weight for 5 treatment cycles during 15 weeks with a total dose of 30 micrograms/g), an antitumor drug, and its effect on the level of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in peripheral tissues. We found that Cisplatin in adult rodents impairs peripheral sensory function and both sympathetic and sensory peripheral innervation as shown by the hot-plate response, catecholamine distribution and substance P immunoreactivity respectively. These changes are associated with decreased NGF in intestine, paws, and bladder while NGF increased in the spinal cord. Also BDNF decreased in bladder and paws and increased in spinal cord and intestine. To further investigate the role of NGF in the pathogenesis of Cisplatin-induced peripheral neuropathies a group of animals was injected with NGF (1 microgram/g every 4 days for 4 times) following Cisplatin treatment and evaluated for sensory function, sympathetic and sensory innervation and BDNF levels. Data demonstrated that exogenous NGF administration is able to restore biochemical, structural and functional changes induced by Cisplatin. These findings suggest that the reduction of NGF availability could be a cause of Cisplatin-induced peripheral neuropathies and that NGF exogenous administration could prevent or reduce Cisplatin neurotoxicity also in cancer patients, reducing the side effects of chemotherapy.

Animals↗

PubMed2000

Interleukin 1beta and GABA-transaminase activity in rat thymus.

The occurrence and distribution of 4-aminobutyrate:2 oxoglutarate transaminase (GABA-t) activity were examined in the rat thymus of normal and immunostimulated rats using biochemical and histoenzymatical methods. Specific GABA-t reactivity was confined primarily to the arteries and, to a lesser extent, to the veins. Only a few activities could be observed in association with the subcapsular and medullar part of the parenchyma and nerve fibers. GABA-t was considered a linking enzyme between the immune and the nervous system and it was studied with the aim of analyzing the relationships between these two systems. Our findings indicate that the GABA-t activity in the thymus is specifically located in the wall of the blood vessels. Moreover, our results demonstrate the presence of a GABA-t activity in the peripheral blood vessels. Treatment with interleukin 1beta induces an increase of protein content of the amounts of GABA-t biochemically assayed and of the levels of histoenzymatically stained GABA-t. Furthermore, staining of the different structures of the thymus in treated or untreated rats shows that the significant modifications concern the parenchyma, the structures resembling nerve fibers and finally, the whole thymus. On the contrary, the highest activity of the GABA-t is located in the walls of arteries, veins and lymphatic vessels.

4-Aminobutyrate Transaminase↗

PubMed2000

Microfilaments in regenerating cells of rabbit cornea: immunological and ultrastructural observations.

The role of myosin-like protein in regenerating and proliferating corneal cells following a standard alkali-injury in the rabbit eye has been studied. Microfilaments were observed by conventional transmission electron microscopy (T.E.M.) in injured epithelium and in fibroblasts. Typical microfilament bundles with electron dense structures and with stress fibers were evident. The presence of myosin-like proteins was demonstrated by means of immunochemical and autoradiographical techniques. Both epithelial cells and fibroblasts bind antimyosin-like antibodies (AMA). The same cells studied with the E.M. showed bundles of microfilaments in the cortical areas of their cytoplasm in correspondence with the same side of fluorescent or labelled AMA. The immunochemical and ultrastructural results suggest that both cells are able to produce in vivo movements involved in morphogenetic phenomena. Therefore, these structures play a role in post-traumatic corneal regeneration.

Actin Cytoskeleton↗

PubMed2000

Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor.

The aim of our study was to explore whether nerve growth factor (NGF) plays any role in the development of peripheral neuropathy induced by anticancer treatment. We measured the circulating NGF levels in 23 cancer patients before and after chemotherapy. We evaluated whether the development of peripheral neurotoxicity was associated with changes in basal NGF concentrations in patients studied with a comprehensive neurological and neurophysiological examination. The results of these studies showed that the circulating levels of NGF, which are about 20 pg/ml in plasma of controls, decrease during chemotherapy and in some cases completely disappeared after prolonged treatment with antitumor agents. The decrease in NGF levels seems to be correlated with the severity of neurotoxicity. These results clearly suggest that NGF might become a useful agent to prevent neuropathies induced by antineoplastic drugs and restore peripheral nerve dysfunction induced by these pharmacological compounds.

Aged↗

PubMed1999

Nerve growth factor: a survey of activity on immune and hematopoietic cells.

Nerve growth factor (NGF) is a well characterized molecule required for the survival and differentiation of a variety of cell types both in the peripheral and central nervous system. Numerous studies published in recent years have demonstrated that NGF affects different functional activities of mature immune and hematopoietic cells. Other studies have revealed that hematopoietic progenitor cells from bone marrow, umbilical cord blood and peripheral blood are receptive to the action of NGF and that bone marrow stromal cells produce/respond to NGF during different steps of normal hematopoiesis. Elevated levels of NGF have been found in a number of inflammatory diseases, including those of autoimmune nature and in myeloproliferative pathologies. This review presents these data and discusses the hypothesis of a possible functional role of NGF in immune and hematopoietic disorders.

Animals↗

PubMed1999

Occurrence of gamma-aminobutyric acid-transaminase activity in nerve fibers of human thymus.

The specific localization of gamma-aminobutyric acid-transaminase (GABA-t) in the thymus of young and elderly men was studied. Our results show a specific vascular localization of GABA-t in the human thymus, and deal with the amount and distribution of GABA-t and its changes with age. Samples of human thymus were harvested throughout of 12 autopsies in infants (n = 3), as well as young (n = 3), adult (n = 3) and elderly (n = 3) men. Histologic staining of the human thymus was performed with eosin-orange, while histologic staining of nerve fibers was performed with the Bodian method. Histochemical and biochemical demonstration of GABA-t, including protein dosage, was performed by the methods of Van Gelder and Jung, respectively. Finally, quantitative analysis of images was performed. Staining with eosin-orange reveals the micro-anatomical details of the thymic micro-environment. The Bodian method shows the nerve fibers and neurofibrils. Histochemical staining for GABA-t shows an increase of this enzyme with age and a marked localization in the nerve fibers of the thymus in infant, young, adult, and elderly men, as well as specific vascular localization of this enzyme. These biochemical data are in accordance with the histoenzymatic results and confirm all of our previous observations. Finally, quantitative analysis of images performed on slices let us confirm all the morphological changes induced by age. We can conclude that GABA is an inhibitory neurotransmitter of the human thymus, while GABA-t plays an important role in GABA metabolism.

4-Aminobutyrate Transaminase↗

PubMed1999

Occurrence of GABA-transaminase in the thymus gland of juvenile and aged rats.

The occurrence and distribution of GABA-transaminase (GABA-t) activity were examined in the thymus of juvenile, adult and aged rats, using enzyme-histochemical and biochemical methods. Quantitative image analysis showed that specific GABA-t reactivity was localized in the wall of the arteries and, to a lesser extent, to the veins. Only a low activity could be observed in association with the subcapsular and medullary part of the parenchyma of the thymus. Many structures resembling nerve fibers also showed low positive reactivity. Biochemical results gave the following decreasing order of GABA-t activity: arteries, veins, whole thymus and parenchyma. Histoenzymatic staining and related values of quantitative analysis of images, are in agreement with the biochemical results; moreover, they demonstrated that the intensity of histoenzymatic staining for GABA-t in thymus of rats strongly decreases with age. GABA-t in thymic tissue is concentrated in blood vessels and particularly in the arteries. Therefore, our findings do not support the earlier assumptions that GABA-t is exclusively concentrated in cerebral vessels. Moreover, the decrease of GABA-t activity during age in thymic tissues may be related to the decrease of thymic microvessels as consequence of the thymic involution. On the contrary, the thymic macrovessels show an elevated staining in all ages with an apparent increase due to the thymic involution.

4-Aminobutyrate Transaminase↗

PubMed1998

Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial.

Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARalpha fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARalpha+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARalpha, as assessed by serial dilution experiments, was 10(-4). All patients were in hematologic remission and tested PCR- at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR- in >/=2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARalpha during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up.

Adolescent↗

PubMed1998

Venous drainage of the stomach in the golden hamster (Mesocricetus auratus) and the guinea pig (Cavia aperea f. porcellus).

Venous drainage patterns of the stomach were studied in 30 golden hamsters (Mesocricetus auratus) and in 30 guinea pigs (Cavia aperea f. porcellus). In golden hamsters the most frequent group had a v. gastroepiploica dextra (85.6% of cases). The v. gastroepiploica sinistra was found in 63.3% of cases. In the second group, the venous drainage pattern was without a v. gastroepiploica dextra (13.3% of cases). The only constant venous channel from the stomach was the v. gastrica sinistra. Other veins draining the stomach were vv. gastricae (tributaries of the v. lienalis) and interorgan venous anastomoses with neighbouring organs. A venous arch along the curvatura ventriculi major was not observed in any of the cases. In the guinea pig, the first group with a v. gastroepiploica dextra accounted for 90.0% of cases while the second group without this vein represented 10.0% of cases. The only constant venous channel was, once again, the v. gastrica sinistra. Other veins of the stomach were similar to those in the golden hamster. A venous arch along the curvatura ventriculi major was found in 76.6% of cases. Some differences in the venous pattern between the two animal species can be explained by zoological differences in these mammals. The results obtained also stimulate interest in the study of possible variations in venous patterns of the stomach in man.

Animals↗

PubMed1998

Cerebral dura mater and cephalalgia: relationships between mast cells and catecholaminergic nerve fibers in the rat.

The aim of the present study was to examine whether mast cells have the same variations as the related catecholaminergic nerve fibers. Chemical sympathectomy or surgical removal of right superior cervical ganglion induced a rapid decrease of fluorescence in both nerve fibers and mast cells, as confirmed by quantitative analysis (nerve fibers 19 +/- 1.1 vs 1.3 +/- 0.6; mast cell 10.8 +/- 1.9 vs 2.1 +/- 0.3). The results of quantitative analysis after nerve fiber stimulation (electrical), however, showed an increase of the fluorescence in both the nerve fibers and the mast cells (nerve fibers 43.4 +/- 2.4; mast cells 18.6 +/- 1.6). Moreover, we found that the basal zone is more innervated (regarding catecholaminergic nerve fibers) than the apical one, and that the fluorescence level decreases passing from the vasal zone to the perivasal and intervasal zones. Further studies are needed in order to clarify the role of fluorescent nerve fibers and mast cells of cerebral dura mater in cephalalgia.

Animals↗

PubMed1998

Catecholaminergic innervation of the human dura mater involved in headache.

The catecholaminergic innervation of cranial dura mater in humans was studied by examining several dural zones (vascular, perivascular, intervascular) in different regions (basal, calvarial, occipital, frontal, tentorial, parietal, temporal). The results demonstrate that catecholaminergic nerve fibers are present in human cranial dura mater and that these fibers, after exposure to formaldehyde vapors, show the specific fluorescence of catecholamines. There are more dural catecholaminergic nerve fibers in the basal region than in the calvarial region. Moreover, these nerve fibers are more abundant in the perivascular dural zone than in the intervascular zone. We hypothesize that these catecholaminergic nerve fibers may be involved in headache.

Aged↗

PubMed1996

Drug-induced changes of carcinoembryonic antigen expression in human cancer cells: effect of 5-fluorouracil.

Previous studies showed that 5-fluorouracil (5-FU) is capable of enhancing the membrane reactivity of the human colon carcinoma cell line HT-29 with a monoclonal antibody (COL-1) directed against carcinoembryonic antigen (CEA). In the present study, we show that short-term exposure (i.e., 1 hr) of cancer cells to 5-FU mediates a marked increase of CEA expression, that is concentration-dependent and lasts up to day 5 after treatment. This phenomenon is the result of the drug-mediated enhancement of the CEA expression, but not of the selection of the CEA-positive cells operated by the antimetabolite. This is supported by the finding that the increase of the CEA expression detected by cytofluorimetric analysis is observed not only in the parental HT-29 line, but also in its C22.20 subclone, endowed with a low basal level of CEA and with chemosensitivity to 5-FU lower than that of the parental cell line. Moreover, increase of CEA expression occurs not only in the plasma membrane, but also in the cytosolic cellular compartment, as indicated by the results of Western blot analysis. Northern blot analysis of total RNA extracted from 5-FU-treated HT-29 or C22.20 cells shows an increase in the steady-state levels of CEA and CEA-related transcripts (e.g., biliary glycoprotein). Moreover 5-FU-mediated augmentation of the CEA transcript appears to be attributable mainly to enhanced transcription rather than to increased mRNA stability. It is concluded that induction of enhanced CEA protein expression in cancer cells treated with 5-FU could be of clinical interest for the development of immunochemotherapeutic protocols based on CEA protein as the target molecule.

Carcinoembryonic Antigen↗