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Biomedical subjects

G Leone

Publications and source records attributed to G Leone.

At least 19 recordsLinked to original sources
PubMed2006

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia.

BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34+ progenitor cells displayed significantly higher BRCA1 expression (P=0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P=0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P=0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P=0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P=0.0004), and to increased DNA methyltransferase DNMT3A (P=0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.

Acute Disease↗
PubMed2006

The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease.

Chronic lymphocytic leukemia (CLL) B-cells are hyporesponsive to many proliferative signals that induce activation of normal B-lymphocytes. However, a heterogeneous response has recently been observed with immunostimulatory CpG-oligodeoxynucleotides (CpG ODN). We now show that CpG ODN induce proliferation mainly in CLL B-cells from patients with progressive disease and unmutated immunoglobulin V(H) genes, whereas G(1)/S cell cycle arrest and apoptosis are induced in leukemic B-cells from stable/V(H) mutated CLL. Examination of early signaling events demonstrated that all CLL B-cells respond to CpG ODN stimulation by degradation of the NF-kappaB inhibitor IkappaB and activation of the Akt, ERK, JNK and p38 MAPK kinases, but the magnitude and duration of the signaling response was greater in the proliferating cases. Pharmacological inhibition of these pathways showed that simultaneous activation of Akt, ERK and JNK is required for cell cycle progression and proliferation. Conversely, introduction of constitutively active Akt in nonproliferating CLL B-cells resulted in induction of cyclin A following CpG ODN stimulation, indicating that increased Akt activation is sufficient to overcome the hyporesponsiveness of these cells to proliferative signals. Thus, the magnitude of Akt signaling may determine the distinct responses observed in leukemic B-cells belonging to the different prognostic subgroups.

Adult↗
PubMed2006

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

Acute Disease↗
PubMed2006

Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis.

Recent efforts have been directed toward new therapeutic options to approach drug-induced hepatitis. We report a case of acute liver failure associated with Nimesulide in a 67-year-old man, with a medical history of chronic alcohol abuse. The biopsy was compatible with chronic alcoholic liver disease and acute drug-induced injury. The patient was enrolled to receive G-CSF followed by apheresis and selection of peripheral-blood stem cells. After ultrasound-guided injection of CD34+cells in the portal vein, we observed a rapid improvement of synthetic liver function, with particular reference to coagulation parameters. Liver biopsy performed 20 days after, showed wide areas of regeneration. In the next 30 days the laboratory signs of acute decompensation progressively improved. Unfortunately he died of multiple-organ failure related to bacterial infection. Intrahepatic injection of peripheral-blood stem cells seemed safe and produced good periprocedural results with improvement of synthetic profile, suggesting a possible role of stem cells in the regeneration process.

Aged↗
PubMed2006

NK/T-cell lymphomas 'nasal type': an Italian multicentric retrospective survey.

OBJECTIVE: To evaluate the clinical characteristics and outcome of NK/T-cell lymphoma 'nasal type' developed in Italian patients. PATIENTS: Between 1997 and 2004, 26 new cases of NK/T-cell lymphoma 'nasal type' were diagnosed in 10 Italian Hematology institutions. RESULTS: All patients were Caucasian, male/female ratio was 19/7, with a median age of 50 years (range 20-80). In 23 cases presentation at the onset was in the nasal cavity or adjacent structures, in two cases the lymphoma onset with skin lesions was followed successively by rhynopharyngeal dissemination, while the remaining case had bone marrow and lymph node involvement followed by oro-pharyngeal involvement. Regarding the stage of disease: 12 patients were in stage I; six in stage II; eight in stage IV. Diagnosis was based on the finding of a NK/T-cell phenotype at the histological and immunophenotypic examination of oropharyngeal or cutaneous lesions. All patients but one were treated with chemotherapy, alone in nine cases or associated to radiotherapy in 14 cases; two patients had chemotherapy, radiotherapy and surgery, while one patient underwent only surgery. Chemotherapy was anthracycline-based in 17 out of 25 cases. In those patients in whom radiotherapy was performed, radiation dosages ranged between 36 Gy and 47.5 Gy, with a median dosage of 40 Gy. Nine patients (34%) were responsive to the treatments: six patients obtained a complete remission and other three a partial remission. The remaining 17 patients resulted refractory or presented a limited response to therapy. The median disease-free survival was 14 months and the median overall survival time was 9 months. CONCLUSION: The results of this retrospective survey confirmed that NK/T-cell lymphoma 'nasal type' is a very rare lymphoma in the Italian population, and it is characterized by a very bad prognosis. Due to the rarity of this disease, a standardized therapeutic approach is lacking. More data are needed to know the epidemiology of this kind of lymphoma in Europe.

Adult↗
PubMed2006

[Peritoneal bleeding due to acquired hemophilia during an abdominal sepsis clinical picture].

Bleeding diatheses are frequent alterations during sepsis and surgical-anesthetic aggression. Generally, the bleeding is related with platelet dysfunction, inadequate surgical hemostasis, vitamin K deficit, etc. We present the case of a patient with no background of coagulopathy who, after two surgical interventions, developed abdominal sepsis and peritoneal hematoma after puncture for drainage of abdominal collection, due to an autoimmune origin factor VIII acquired deficit. The hematoma caused a picture of hypovolemic shock that required transfusion of several units of red blood cells, expansion and drug support. Finally, the bleeding was controlled by treatment with immunosuppressants, recombinant activated factor VII (RFVIIa) and polyvalent gammaglobulin. The peritoneal hematoma was drained surgically and the patient evolved towards improvement until being discharged from the intensive therapy unit.

Adult↗
PubMed2006

Tacalcitol and narrow-band phototherapy in patients with vitiligo.

BACKGROUND: Vitiligo is a skin disease characterized by loss of normal pigmentation in the skin. Several treatments exist but none is really effective. Recently, perturbations of calcium homeostasis in vitiliginous epidermis have been described. AIM: Based on these findings, the aim of this prospective, randomized, open-label study was to compare the effectiveness of narrow-band ultraviolet B (NB-UVB) phototherapy alone and the combination of NB-UVB and topical application of the vitamin D(3) analogue tacalcitol in the treatment of vitiligo. METHODS: In total, 32 subjects with generalized vitiligo and symmetrical lesions were enrolled in the study. Subjects were instructed to apply tacalcitol ointment daily to the lesion on the side randomly selected to receive combination therapy. All subjects received NB-UVB phototherapy on a twice-weekly schedule. RESULTS: Addition of topical tacalcitol to NB-UVB treatment improved the extent of repigmentation and increased the response rate in patients with vitiligo compared with NB-UVB treatment alone. CONCLUSION: Application of tacalcitol ointment in combination with twice-weekly NB-UVB phototherapy is an effective alternative treatment for patients with generalized vitiligo.

Administration, Cutaneous↗
PubMed2006

Aetiological factors related to a positive direct antiglobulin test result in human immunodeficiency virus-infected patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to examine the clinical importance and causes of a positive result in the direct antiglobulin test (DAT) in human immunodeficiency virus-infected (HIV(+)) patients. We therefore studied haematological parameters in outpatient samples, and also analysed the impact of highly active anti-retroviral therapy (HAART) on the DAT results. STUDY DESIGN AND METHODS: Haematological parameters, clinical stages, chemo-antibiotic treatments and HAART treatment were studied to determine any relationships with DAT results in 115 consecutive HIV(+) patients. RESULTS: Significantly lower haemoglobin (Hb) levels were detected in patients with HIV who had a positive DAT result. Hepatitis C virus (HCV) co-infection (odds ratio 2.529) and trimethoprim-suphamethoxazfole (TMP-SMX) prophylaxis (odds ratio 3.751) had a significant association with DAT positivity. Patients receiving HAART were less likely to have a positive DAT [odds ratio (OR) 0.383; P = 0.035]. Among the patients treated with TMP-SMX, those with a positive DAT had lower Hb levels (11.9 g/dl) than those with a negative DAT (14.2 g/dl; P = 0.04). HCV antibody positivity and TMP-SMX prophylaxis showed a cumulative effect on positive DATs (OR 4.533). The surface exploratory analysis indicated the distribution of the positive DATs in relationship with the CD4(+) count and Hb levels. CONCLUSIONS: Significantly lower Hb levels were detected in DAT-positive HIV(+) patients. HCV co-infection and TMP-SMX prophylaxis appear to confer an increased risk of DAT positivity. The presence of red blood cell autoantibodies may be associated with anaemia in HIV disease in the absence of overt haemolysis.

Anemia↗
PubMed2006

Fungal pneumonia due to molds in patients with hematological malignancies.

Invasive fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. In particular, patients with neutropenia and those who have undergone allogeneic hematopoietic stem cell transplantation are at highest risk, with fungal pneumonia being the main clinical manifestation in these patients. The most common pathogens associated with fungal pneumonia are Aspergillus spp. and Zygomycetes. However, other pathogens have also been observed in fungal pneumonia, including Cryptococcus spp., Pneumocystis jirovecii, and Candida spp. This comprehensive review will focus on the important practical aspects relevant to the epidemiology, clinical diagnosis, and therapeutic management of pneumonia due to filamentous fungi in patients affected by hematological malignancies.

Amphotericin B↗
PubMed2006

Treatment of acute leukaemias with monoclonal antibodies: current status and future prospects.

Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to direct cellular effects, antibodies can carry substances to the targeted cells, such as radioactive isotopes, toxins, and antineoplastic agents. At present monoclonal antibodies, directed against both lymphoid antigens (CD 20 and CD 52) and a myeloid antigen (CD33) are available for clinical use. In ALL, rituximab, a humanized anti CD20 antibody, has been combined to chemotherapy mainly in mature B-ALL and Burkitt's lymphoma and preliminary results are promising. Alemtuzumab is an anti-CD52 humanized antibody, which showed anti-tumour activity in CLL; clinical effects were observed in some patients with relapsed adult ALL. Monoclonal antibodies against myeloid antigens have been prevalently used in acute myeloid leukaemias (AML), where the most utilised immunological target is CD33. The CD33 molecule is expressed by approximately 90% of AMLs but not on CD34(+) bone marrow-resident hematopoietic stem cells. The humanized anti-CD33 monoclonal antibody HuM195 has only modest activity against overt AML, but it can eliminate minimal residual disease. Radioimmunotherapy with beta-particle-emitting isotopes targeting CD33 shows a major efficacy. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin (GO) has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy. GO is composed of a humanized immunoglobulin G(4) (IgG(4)) monoclonal antibody (mAb), targeting the CD33 antigen and linked to a calicheamicin derivative, a cytotoxic anthracycline antibiotic. GO has been approved by FDA as second-line therapy in older patients with AML. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumour lysis syndrome. Alemtuzumab causes immunosuppression, increasing the risk of infection. GO may cause hepatotoxicity.

Acute Disease↗
PubMed2005

How does human stem cell therapy influence gene expression after liver injury? Microarray evaluation on a rat model.

BACKGROUND: Tissue homeostasis is guaranteed by stem proliferating reserve, depending on dynamic changes in gene expression. A high plasticity is shown by the haematopoietic stem cells, potential source for liver regeneration. AIM: We aimed to evaluate the gene expression modifications induced by human haematopoietic stem cell therapy after liver injury in rats. SUBJECTS: Rats were sorted as follows: (A) human-haematopoietic stem cell injection after allyl alcohol liver damage; (B) only haematopoietic stem cell injection; (C) only allyl alcohol injection; and (D) sacrifice without any treatment. METHODS: Livers, spleens and bone marrows were analysed with flow-cytometry. Livers were also studied by reverse-transcription PCR, histology, immunohistochemistry and microarray analysis; selected genes were confirmed by real-time PCR. RESULTS: In subset A, haematopoietic stem cells were selectively recruited by liver, with respect to the group B, and they improved the liver regeneration process compared to group C. As regards microarrays, haematopoietic stem cell infusion upregulates 265 genes and downregulates 149 genes. Differentially regulated genes belong to a broad range of functional pathways, including proliferation, differentiation, adhesion/migration and transcripts related to oval-cell activation. Real-time PCR validated array results. CONCLUSIONS: Our study confirmed the capacity of haematopoietic stem cells to contribute to liver regeneration. Moreover, microarray analysis led to the identification of genes whose regulation strongly correlates with a more efficient process of liver repair after haematopoietic stem cell injection.

Animals↗
PubMed2005

Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study.

The authors performed a double-blind, placebo-controlled study in 28 patients to evaluate the effects of sildenafil on cerebral hemodynamics. A significant improvement of cerebrovascular reactivity, without any modification of other variables, was recorded 1 hour after the administration of 50 mg sildenafil. Further investigations are needed to evaluate whether cerebrovascular reactivity improvement could contribute to triggering sildenafil-induced migraine.

Aged↗
PubMed2005

Subacute demyelinating polyneuropathy in B-cell lymphoma with IgM antibodies against glycolipid GD1b.

Peripheral neuropathy associated with IgM monoclonal gammopathy of unknown significance is a common disorder, while the association of paraproteinaemic neuropathies with haematological malignancies is far less frequent. We report a 76-year-old patient with a subacute and rapidly progressive sensorimotor demyelinating polyneuropathy causing sensory ataxia, painful paraesthesias and marked motor and sensory deficit in four limbs. Monoclonal gammopathy of IgM type associated with a rectal low-grade B-cell non-Hodgkin lymphoma was detected. Research for anti-MAG and antiganglioside autoantibodies including anti-GM1 and anti-GQ1b evidenced a high titre of IgM antibodies against the disialosyl group of GD1b. This is the first report on a paraproteinaemic polyneuropathy with IgM autoantibodies against glycolipid GD1b associated with B-cell lymphoma. The IgM type of these autoantibodies suggests that they represent all or part of the paraprotein produced by lymphoma cells.

Aged↗
PubMed2005

Blood vessel formation after soft-tissue implantation of hyaluronan-based hydrogel supplemented with copper ions.

The possibility of ameliorating bone healing of implanted bone allografts is a field of great interest. Early vascular invasion is a key factor in bone allograft incorporation. It is well known that copper ions (Cu2+) show a proangiogenic action favouring the development of new vessels. In this work a hyaluronan based 50% hydrogel (Hyal-50%) was enriched with (Cu2+) and its proangiogenic activity was evaluated. Fifteen Sprague Dawley female rats were submitted to the subcutaneous implantation of Hyal-50%, freeze-dried bone allografts, Hyal-50%-Cu2+, freeze-dried bone allografts plus Hyal-50% and freeze-dried bone allografts plus Hyal-50%-Cu2+. One month later, histomorphometric analysis evidenced the presence of a fibrous-reactive capsule around all specimens showing significant differences among groups (p<0.0005). The highest thickness of the fibrous capsule was found around the freeze-dried bone implants (p<0.05); as well as the Hyal-50%-Cu2+ plus freeze-dried bone (15.2%, p<0.05) and Hyal 50% plus freeze-dried bone (21.4%, p<0.0005) implants showed a significant higher thickness compared with Hyal 50% and Hyal-50%-Cu2+. Statistical analysis showed a significant (p<0.01) higher vascular density in Hyal- 50%-Cu2+ and Hyal-50%-Cu2+ plus freeze-dried bone group when compared to other groups. The present preliminary results suggest the advantages offered by the combined use of a well-known biocompatible and tissue healing promoting material (Hyal-50%) and a new technique that consists of stimulating tissue vascularization using Cu2+ and that bone allograft incorporation may benefit from this technology.

Animals↗