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Biomedical subjects

L Marcucci

Publications and source records attributed to L Marcucci.

At least 19 recordsLinked to original sources
PubMed2006

First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer.

BACKGROUND: We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients. METHODS: Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44-75), ECOG PS>or=1 21 (39%) patients, multiple sites of disease 33 (61%) patients. RESULTS: A median of 4.1 months of second-line chemotherapy per patient were administered (range 1-8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months. CONCLUSIONS: First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.

Adult↗
PubMed2004

First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule.

BACKGROUND: In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings. PATIENTS AND METHODS: A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks. RESULTS: All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months. CONCLUSIONS: This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.

Adult↗
PubMed2004

Chromosome instability in T-cells cultured in the presence of pancuronium or fentanyl.

BACKGROUND: Genomic instability is recognized as a cause of cellular apoptosis and certain drugs that exhibit a proapoptotic effect are also able to induce chromosome damage. Since we found in recent experiments that drugs such as pancuronium and fentanyl exerted an apoptogenic effect on T cells, we studied the capacity of those agents to promote chromosome instability, i.e. chromosome aberrations (CA) and telomeric associations (tas) in peripheral blood lymphocytes. METHODS: Lymphocytes from healthy donors were cultured with pancuronium or fentanyl, using two different concentrations for each drug: 20 and 200 ng/ml for pancuronium and 10 and 30 ng/ml for fentanyl, respectively. Cells were exposed to each concentration of these drugs either for 24 or 48 h. The higher concentration chosen was the same at which we detected the proapoptotic effect in our previous works. Cytogenetic analysis was performed by means of a standard technique and chromosome aberrations or telomeric associations were blindly evaluated by two independent observers. RESULTS: The chromosome aberrations we observed in treated cells were not significantly different from control lymphocytes. However, an unusual rate of telomeric associations (P < 0.001) was detected in cells exposed to both pancuronium and fentanyl, at each concentration tested and at each exposure time of the study. CONCLUSIONS: Fentanyl and pancuronium do not have a direct clastogenic effect on T cultures, but at the same concentrations at which we demonstrated their apoptogenic power, these drugs are able to increase genomic instability through inducing an elevated rate of telomeric associations. Such a capacity could exploit in peripheral T cells the same mitochondrion-mediated signal pathway of apoptosis death.

Adult↗
PubMed2003

Telomerase activity, apoptosis and cell cycle progression in ataxia telangiectasia lymphocytes expressing TCL1.

Individuals affected by ataxia telangiectasia (AT) have a marked susceptibility to cancer. Ataxia telangiectasia cells, in addition to defects in cell cycle checkpoints, show dysfunction of apoptosis and of telomeres, which are both thought to have a role in the progression of malignancy. In 1-5% of patients with AT, clonal expansion of T lymphocytes carrying t(14;14) chromosomal translocation, deregulating TCL1 gene(s), has been described. While it is known that these cells can progress with time to a frank leukaemia, the molecular pathway leading to tumorigenesis has not yet been fully investigated. In this study, we compared AT clonal cells, representing 88% of the entire T lymphocytes (AT94-1) and expressing TCL1 oncogene (ATM(-) TCL1(+)), cell cycle progression to T lymphocytes of AT patients without TCL1 expression (ATM(-) TCL1(-)) by analysing their spontaneous apoptosis rate, spontaneous telomerase activity and telomere instability. We show that in ATM(-) TCL1(+) lymphocytes, apoptosis rate and cell cycle progression are restored back to a rate comparable with that observed in normal lymphocytes while telomere dysfunction is maintained.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Telomeric associations and chromosome instability in ataxia telangiectasia T cells characterized by TCL1 expression.

T-cell tumors in ataxia telangiectasia (AT), such as T-PLL/T-CLL, are first preceded by the development of a large clone of T-lymphocytes, characterized by chromosomal rearrangements, which usually involve specific regions such as the 14q11 region. Malignancy develops years later, after additional chromosomal changes resulting from the genomic instability consequent to ATM disruption and to the activation of the TCL1 oncogene. Here we report the results of a cytogenetic follow-up of an AT patient (AT94-1), still without signs of hematological abnormalities, bearing a T-lymphocyte clone characterized by the t(14;14)(q11;q32) rearrangement and having TCL1 expression. We demonstrated that in clonal cells TCL1 expression correlates with increasing genomic instability and in time this mainly induces chromosomal rearrangements and telomeric associations (tas). Chromosome 21 is not randomly involved; in particular, an i(21q) indicates that it is a subclone prone to additional genetic changes and could represent an early chromosomal rearrangement involved in tumorigenesis. With regard to the increase in tas, we observed that: (i) it is inversely correlated with the proliferative ability of AT94-1 lymphocytes in PHA-stimulated short-term cultures (cell aging in vitro); (ii) this increase is not due to changes either in cell radiosensitivity (measured as bleomycin (BML)-sensitivity) or due to an illegitimate recombination (measured as adriamycin-sensitivity), which may not be sufficient for tumor development.

Adult↗
PubMed2000

Chromosomal alterations and male infertility.

Reduced male fertility can be caused by genetic factors affecting gamete formation or function; in particular, chromosome abnormalities are a possible cause of male subfertility as shown by their higher frequency in infertile men than in the general male population. Meiotic studies in a number of these males have shown spermatogenesis breakdown, often related to alterations in the process of chromosome synapsis. Indeed, any condition that can interfere with X-Y bivalent formation and X-chromosome inactivation is critical to the meiotic process; furthermore, asynapsed regions may themselves represent a signal for the meiotic checkpoint that eliminates spermatocytes with synaptic errors. We performed cytogenetic, hormonal and seminal studies in 333 infertile patients selected because azoospermic, severely oligozoospermic or normozoospermic with failure to fertilize the partner's oocytes in an in vitro fertilization (IVF) program. Our findings: 1) confirm the high incidence of chromosomal anomalies among infertile males; 2) highlight the relevance in male infertility of quantitative/positional modifications of the constitutive heterochromatin; and 3) underline the relevance of cooperation between andrologists and cytogenetists prior to every kind of assisted reproduction, above all prior to intracytoplasmic sperm injection, in which selective hurdles eliminating abnormal germ cells are bypassed.

Adult↗
PubMed1999

Supraceliac aortic pseudoaneurysms after liver transplantation in infants.

BACKGROUND: Reconstruction of the hepatic artery in infants undergoing liver transplantation presents challenging vascular situations. Microvascular techniques ensure arterial blood flow via small caliber vessels but are insufficient when inflow is poor. In these situations, the use of allogeneic grafts to the supraceliac aorta have been advocated. The development of a pseudoaneurysm at the supraceliac aortic suture line requires urgent repair and restoration of arterial flow to the graft. METHODS: Our study was based on case reports and review of the literature. RESULTS: Definitive diagnosis and successful repair of supraceliac pseudoaneurysm was accomplished in two infants after transplantation. CONCLUSION: We advocate a thoracoabdominal retroperitoneal approach, which provides safe control of the aorta and primary repair or patching of the diseased aortic segment, and also provides access for hepatic revascularization via placement of an infrarenal graft. Thrombosis of the artery and subsequent liver necrosis are indications for retransplantation.

Aneurysm, False↗
PubMed1998

A synthetic CD4-CDR3 peptide analog enhances skin allograft survival across a MHC class II barrier.

The efficacy of a synthetic peptide analogue (rD-mPGPtide), mimicking the CDR3 region in the first domain of the CD4 surface molecule, was investigated in a murine model for CD4+ T cell-mediated skin allograft rejection. A single injection of rD-mPGPtide shortly before transplantation exhibited significantly prolonged graft survival in the B6 anti-B6.C-H2bm12 MHC class II-disparate strain combination. Long-term graft survival (>100 days) was achieved when thymectomized adult recipient mice were transplanted along with rD-mPGPtide treatment. The peptide also affected secondary rechallenge responses with MHC class II allografts. In addition, the inhibitory effect of the rD-mPGPtide in this transplantation model was directed against CD4+ T cells and was exclusively specific toward donor alloantigen. In vitro analysis of CD4+ T cells isolated from the draining lymph nodes of rD-mPGPtide-treated recipients indicated a 450-fold decrease in precursor frequency in response to donor allostimulation compared with the untreated control group. There was also significant down-regulation of the frequency of IL-2-, IFN-gamma-, and IL-4-producing CD4+ T cells upon in vitro allogeneic restimulation of host cells 4 days posttransplantation. However, these same CD4+ T cells maintained the capacity to produce normal cytokine levels upon third-party allostimulation. Thus, these studies demonstrate that a CD4-CDR3 peptide analogue can specifically and effectively prolong skin graft survival across MHC class II barriers.

Animals↗
PubMed1998

Effects of poly(ADP-ribose) polymerase inhibition on cell death and chromosome damage induced by VP16 and bleomycin.

Poly(ADP-ribose) polymerase (PARP) is a DNA-binding protein involved in cellular response to various genotoxic agents. To understand the role of PARP in the mechanisms which lead from specific DNA damage to cell death, we studied the effects of PARP inhibition in human lymphoblasts damaged with bleomycin (BLM) and VP16. These agents can induce DNA breakage but through different mechanisms, enabling the study of the different effects of PARP in inducing apoptosis in damaged cells. We demonstrate that in lymphoblasts VP16 treatment induces apoptosis to a greater extent than BLM treatment, and that PARP inhibition reduces VP16-induced apoptosis whereas it has no effect on BLM-induced apoptosis. After VP16 treatment with PARP inhibition, a reduction in the depletion of the proliferative compartment and a G2/M phase arrest are observed. Therefore, the increase in cell viability and the reduction in chromosome damage may both be the result of a prolonged DNA repair time. Hence, PARP appears to play a significant role in VP16-induced apoptosis and not in BLM-induced apoptosis. Since apoptosis is important in tumor treatment these findings might be useful when considering the combined employment of PARP inhibition with antineoplastic drugs.

Apoptosis↗
PubMed1998

[Repetitive release of the medial nerve in the carpal tunnel. Analysis of a series of 18 cases].

PURPOSE OF THE STUDY: This study analyzes 18 revision procedures for carpal tunnel release failure. MATERIAL: This series did not present any difference in terms of age compare to the population suffering from median nerve entrapment: mean age 56 years, 17 female and 1 male, 1 monolateral syndrome and 8 bilateral. Two third of the patients were seen between 2 and 9 months after initial surgical treatment. Most of the first surgical procedures were performed by an orthopedic surgeon (12/18). The approach was open (14/18) with 5 short incisions, and 4 endoscopic releases. Clinical symptoms were worse or unchanged compare to prior to surgery. All the patients had EMG study and 15 had worse electric signs than before. Open surgical approach was always palmar using optic magnification for median nerve neurolysis. RESULTS: 16 times an incomplete section of the anterior retinaculum and 2 median nerve lacerations were found. All patients were seen with a follow up of more than 2 months. Results concerning pain and sensibility were good for 16 of them; regarding motor impairment, only 13 of them had a good result. Grasp was not improved for 50 per cent of them. Two patients had a result considered as bad (one NAD sequela and one median total laceration). DISCUSSION: In our series as well as in literature, failures of carpal tunnel release are due to incomplete section of the anterior retinaculum and sometimes to median nerve laceration. The second look has to be performed when there is no improvement or when the situation is worse after initial surgery. CONCLUSION: Incomplete section of the anterior retinaculum is the most frequent reason for carpal tunnel release failure. An EMG seems necessary to confirm diagnosis before revision surgical procedure.

Aged↗
PubMed1997

[Primary metacarpophalangeal and proximal interphalangeal arthrosis of the hand. Indications and results of 27 DJOA arthroplasty].

The authors report 27 Digital Joint Arthroplasties (DJOA), implanted exclusively in cases of osteoarthritis, between 1985 and 1994. The metacarpophalangeal joint was involved in 8 cases and the proximal interphalangeal joint was involved in 19 cases in a series of 20 patients with a mean age of 58 years (49-84). The mean interval between the first clinical signs and the surgical operation was 34 months (12-72). An anterolateral incision was used in 5 cases for the PIP joint, and an anterior incision was used in one case for the MP joint. All other cases were operated via a dorsal incision. Two early complications were observed: septic ulceration of the skin and dislocation of the PIP prosthesis on the 8th day. Good results were obtained in terms of pain. Range of movement was only slightly improved by arthroplasty and exclusively in the extension sector. The range of movement of the MP joint increased from 35 degrees to 50 degrees, while the range of movement of PIP joint remained unchanged at 50 degrees with a slight displacement of 5 degrees towards the extension sector. This can be explained by the radiological follow-up of our implants which showed impaction of the prosthetic shaft during the first two postoperative years with appearance of signs of periarticular ossification. The results concerning range of movement and pain were analogous to those of other series in the literature, particularly with the use of Swanson implants. On the other hand, DJOA arthroplasty presents a low incidence of axial deviation problem (1 case out of 27). The authors are currently trying to improve the results of DJOA arthroplasty by creating a size 0 to suit anatomical requirements and by adopting the anterolateral incision to preserve the extensor apparatus in order to decrease postoperative flexion deformity.

Aged↗
PubMed1996

Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes.

DNA topoisomerase II is involved in DNA topologic changes through the formation of a cleavable complex. This is stabilized by the antitumor drug VP16, which results in DNA breakage, aberrant recombination, and cell death. In this work, we compare the chromosomal damage induced by VP16 with that induced by bleomycin (BLM) in lymphoblasts from patients affected by the chromosome breakage syndromes ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Bloom syndrome (BS), and by the progeroid syndromes Werner (WS) and Cockayne (CS). Patients affected by AT, XP, BS, and WS have a greatly enhanced risk of developing cancer. The results show that AF and WS cells are hypersensitive to VP16, as revealed in the higher proportion of metaphases showing exchange figures and more than two breaks. All lines except AT and one CS line showed normal sensitivity to BLM. Our data on the sensitivity to VP16 of all these mutant cells underline the fact that VP16 damage is amplified only in cells that have abnormal illegitimate recombination (i.e., AT and WS).

Ataxia Telangiectasia↗
PubMed1996

VP16 hypersensitivity and increased faulty recombination in ataxia telangiectasia lymphocytes characterized by the tandem translocation t(14;14)(q11;q32).

Ataxia telangiectasia (AT) patients show variable degrees of immunodeficiency and a higher than normal predisposition to lymphoid malignancies. AT cells are characterized by spontaneous chromosome instability resulting in chromosome breakage and in non random chromosome rearrangements. Sequential cytogenetic studies on T-lymphocytes from an AT patient showed the progressive development of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosome rearrangements. Compared to non clonal cells, the abnormal clone displayed a higher frequency of spontaneous chromosome rearrangements. In only the clonal cells we observed two particular and predominant rearrangements: isodicentric chromosomes and telomeric associations which may derive from faulty recombination. Chromosome instability induced by the etoposide VP16, a DNA topoisomerase II inhibitor, was evaluated in terms of chromosome breakage and SCE frequency. T-lymphocytes from the AT patient showed hypersensitivity to VP16 significantly higher than normal T-lymphocytes. The chromosome instability induced by VP16 is significantly higher in clonal than in non clonal cells, whilst the chromosome instability induced by the radiomimetic drug bleomycin is not significantly different in the two AT lymphocyte subpopulations. The different spontaneous chromosome instability in clonal and non clonal cells together with their different behavior after treatment with only VP16, suggest that clonal cells bearing the tandem translocation could have increased faulty recombination. Given the presence of translocations t(14;14)(q11;q32) in T-prolymphocytic leukemias and T-cell tumors of non AT patients, our findings suggest that VP16 could be considered an antineoplastic treatment particularly indicated in these patients.

Adolescent↗
PubMed1994

Expression of genes carried by pR plasmid in damaged E. coli and mouse cells.

In LTA mouse cells pR plasmid constitutively expresses itself resulting in protection against typical SOS inducers (UV, 4NQO) and in sensitization to different DNA-damaging agents (MNNG, cisDDP, BLM and geneticin (G418). The pR sensitizing effect is specific to mammalian cells, since the plasmid can only protect prokaryotic cells against the damaging agents tested. The pR protecting effect requires the expression of both the uvp1 and uvp2 (mucAB) regions in bacteria as well as in mouse cells. The coordinated function of these regions could result in protection against typical SOS inducers through an SOS/SOS-like pathway. The sensitization conferred by pR plasmid depends mostly on the expression of the mucAB genes, as shown by the survival of mouse cells transfected with different pR::Tn5 mutants. In particular, BLM and G418 survival data demonstrate that, inserted into the pR plasmid, the ble and neo genes of the Tn5 transposon express themselves. This was confirmed by the presence of Tn5 transcripts in untreated mouse cells. The comparison between the pR effects in bacterial and mouse cells shows that during evolution the repair pathways against UV damage are better conserved than those against other kinds of damage.

4-Nitroquinoline-1-oxide↗
PubMed1993

Neurological and cytogenetic study in early-onset ataxia-telangiectasia patients.

The clinical diagnosis of ataxia-telangiectasia (AT) is difficult before the age of 4 years. We report clinical and cytogenetic data on three early-onset, early-diagnosed AT patients at the age of 12, 18 and 22 months, respectively. Postural instability of the trunk, characterized by motor impersistence, was the earliest neurological sign detected as early as 1 year of life. Dystonic movements and postures of arms and trunk and a subtle disorder of eye movement (blinking before gaze changing, increased latency and dysmetry of saccades) were observed during the 2nd year of life. All patients exhibited an unusual temper tantrum. We also observed an increased bleomycin-induced chromosomal instability in patient's cells in the early stages of the disease before all the clinical hallmarks were apparent. Our data suggest that detection of clinical indications, leading to early laboratory confirmation of AT, can reduce the age at diagnosis.

Adolescent↗
PubMed1993

[The treatment of ENT phlogosis: seaprose S vs. nimesulide].

In the present multicentre study, the antiphlogistic activity of seaprose S was assessed according to an experimental design of the controlled type versus nimesulide in patients with phlogistic pathology of ENT relevance and in patients undergoing otoiatric surgical operations. One hundred and sixty patients (87 M, 73 F) were treated with seaprose S in 30 mg tablets (3tab/day) while 160 patients (95 M, 65 F) were treated with nimesulide in 100 mg (2 tab/day). The treatment lasted 7 days. At the beginning of the study, on the 3rd, 7th and 14th day (follow-up) the most significant signs and symptoms present in the pathological forms under consideration were evaluated. Common haematological and haematochemical laboratory parameters were also evaluated and any side effects occurring during the treatment were recorded. Considering the efficacy demonstrated, it was shown how the two drugs used possess an analogous action (NS) and are always able to exert positive control over the symptoms under examination. Administering seaprose S there were 9 cases of unexpected events (5.6%) while with nimesulide 26 patients (16.3%) showed problems of intolerance, with a highly significant statistical difference (p < 0.01) between the two groups. The analysis of the data obtained allows us thus to support the therapeutic use of seaprose S in the treatment of phlogosis of ENT relevance, since it has shown efficacy comparable to that of a NSAID such as nimesulide, but with greater safety.

Adolescent↗
PubMed1992

Heterogeneity in ataxia-telangiectasia: classical phenotype associated with intermediate cellular radiosensitivity.

We identified a subgroup of ataxia-telangiectasia (AT) patients (2 sibs and 1 unrelated case) characterized by typical clinical manifestations of the disease and cellular radiosensitivity intermediate between classical AT and normal subjects. Our data and a literature review of the intermediate radiosensitivity AT cases show that radioresistant DNA synthesis, cellular radiosensitivity (measured in terms of survival and chromosome breakage), and the clinical hallmarks behave independently. This raises a number of interesting questions about the correlation between radiobiological and clinical features, and about the nature of the AT gene(s).

Adolescent↗