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Biomedical subjects

M Ponzoni

Publications and source records attributed to M Ponzoni.

At least 37 records · Page 2Linked to original sources
PubMed2001

Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients.

OBJECTIVES: To assess the feasibility and the activity, as well as the efficacy to treat meninges, of chemotherapy (CHT) containing high-dose methotrexate (HD-MTX) followed by radiation therapy (RT), without intrathecal CHT, in patients with primary central nervous system lymphoma. METHODS: Eligibility criteria were histologically proven diagnosis, disease limited to the CNS, age < or = 70, ECOG performance status < or = 3, HIV-negative and no prior treatment. Thirteen patients (1996-1999; median age 54 years) received two courses of vincristine 1.4 mg/m2 day 1, MTX 3 g/m2 days 3 and 10 and procarbazine 100 mg/m2 days 1-14 every 4 weeks. Patients who achieved a complete remission were referred to RT, those with progressive disease were excluded from further study; all the remaining patients received a third course of CHT followed by RT. RESULTS: Twelve patients responded to CHT (overall response rate = 92%, complete response rate = 77%): 9 underwent consolidation RT, 3 did not. Two patients experienced severe acute toxicity; lethal pulmonary thromboembolism and transient renal failure. Five patients relapsed: 2 after CHT and 3 after RT. Relapse was local in all cases, with a case of concomitant hepatic involvement. No cases of ocular or meningeal relapse were observed. In contrast to high-dose cytarabine-containing CHT, salvage therapy with temozolomide produced good results. Two patients died of treatment-related neurotoxicity. Six patients are alive with a median follow-up of 17 months, and a 2-year overall survival (OS) of 61%. The median survival of the 9 patients who completed the planned treatment is 25+ months with a 2-year OS of 80%. CONCLUSIONS: HD-MTX, procarbazine and vincristine followed by RT, without intrathecal therapy, produce similar results with respect to other HD-MTX-containing regimens. These results seem to suggest that adequate meningeal treatment is possible without intrathecal drug delivery, even in CSF-positive patients. Corroborating data from a larger series are, however, necessary. Temozolomide should be tested in relapsed patients in a phase II prospective trial.

Adult↗
PubMed2001

Primary granulocytic sarcoma presenting with bone pain and hypergammaglobulinemia.

Granulocytic sarcoma (GS), is an extramedullary tumorous aggregate of neoplastic myeloid precursor cells, most often associated with acute myeloid leukemia (AML). Primary GS occurs in patients with normal bone marrow and no history of hematological disorders. It is a rare disease, which can involve any organ and mimic other tumors. A correct initial diagnosis, which can be difficult, and early treatment with chemotherapy as for AML patients results in a higher rate of complete remission. We report a case of multifocal primary GS of the bone associated with oligoclonal hypergammaglobulinemia, successfully treated with AML-like induction chemotherapy followed by postinduction therapy with autologous peripheral stem cells transplantation. The possible significance of the associated hypergammaglobulinemia is discussed.

Acute Disease↗
PubMed2000

Delivery of c-myb antisense oligodeoxynucleotides to human neuroblastoma cells via disialoganglioside GD(2)-targeted immunoliposomes: antitumor effects.

BACKGROUND: Advanced-stage neuroblastoma resists conventional treatment; hence, novel therapeutic approaches are required. We evaluated the use of c-myb antisense oligodeoxynucleotides (asODNs) delivered to cells via targeted immunoliposomes to inhibit c-Myb protein expression and neuroblastoma cell proliferation in vitro. METHODS: Phosphorothioate asODNs and control sequences were encapsulated in cationic lipid, and the resulting particles were coated with neutral lipids to produce coated cationic liposomes (CCLs). Monoclonal antibodies directed against the disialoganglioside GD(2) were covalently coupled to the CCLs. (3)H-labeled liposomes were used to measure cellular binding, and cellular uptake of asODNs was evaluated by dot-blot analysis. Growth inhibition was quantified by counting trypan blue dye-stained cells. Expression of c-Myb protein was examined by western blot analysis. RESULTS: Our methods produced GD(2)-targeted liposomes that stably entrapped 80%-90% of added c-myb asODNs. These liposomes showed concentration-dependent binding to GD(2)-positive neuroblastoma cells that could be blocked by soluble anti-GD(2) monoclonal antibodies. GD(2)-targeted liposomes increased the uptake of asODNs by neuroblastoma cells by a factor of fourfold to 10-fold over that obtained with free asODNs. Neuroblastoma cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes containing c-myb asODNs than by nontargeted liposomes or free asODNs. GD(2)-targeted liposomes containing c-myb asODNs specifically reduced expression of c-Myb protein by neuroblastoma cells. Enhanced liposome binding and asODN uptake, as well as the antiproliferative effect, were not evident in GD(2)-negative cells. CONCLUSIONS: Encapsulation of asODNs into immunoliposomes appears to enhance their toxicity toward targeted cells while shielding nontargeted cells from antisense effects and may be efficacious for the delivery of drugs with broad therapeutic applications to tumor cells.

Antibodies, Monoclonal↗
PubMed2000

Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis.

Intravascular Lymphomatosis (IL) is a rare and usually aggressive form of non-Hodgkin's lymphoma characterized by the growth of neoplastic cells within vascular lumina that usually presents with skin or central nervous system (CNS) involvement. The mechanism(s) for the selective intravascular growth of this neoplasm remain(s) unexplained. We now report clinical and immunohistologic data on surgical material from 6 cases of IL; in 4 of 6 cases, autopsies were performed. Our IL cases shared the following features: (1) B-cell lineage; (2) lack of skin involvement at presentation; (3) aggressive behavior; and (4) lack of extravascular lymphomatous masses; in addition, 1 case had an associated gastric low-grade MALT lymphoma. We studied by immunohistochemistry formalin-fixed, paraffin-embedded sections with monoclonal antibodies to molecules known to be involved in lymphocyte and endothelial adhesion phenomena, that is, CD29 (beta1 integrin subunit), CD43 (leukosialin), CD44 (H-CAM), CD54 (ICAM-1), embryonal N-CAM (e-NCAM), and EMA (episialin). In all cases, the surfaces of IL aggregates reacted for CD44 but were consistently negative for CD29; also absent was CD54. Conversely, the integrity of the endothelial cells was underscored by their even reactivity for CD29, CD44, and CD54. Given that CD29 is currently regarded as critical for lymphocyte trafficking in general and for transvascular migration in particular, and CD54 is also involved in transvascular lymphocyte migration, we conclude that their consistent absence in IL may contribute to its intravascular and disseminated distribution pattern. The rather frequent association of IL with various conventional lymphomas is known; yet, one of our cases appears to be the first report of IL associated with a low-grade MALT lymphoma.

Aged↗
PubMed2000

Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas.

BACKGROUND: To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.

Adult↗
PubMed1999

Autocrine regulation of volume-sensitive anion channels in airway epithelial cells by adenosine.

The activity of volume-sensitive Cl- channels was studied in human tracheal epithelial cells (9HTEo-) by taurine efflux experiments. The efflux elicited by a hypotonic shock was partially inhibited by adenosine receptor antagonists, by alpha,beta-methyleneadenosine 5'-diphosphate (alphabetaMeADP), an inhibitor of the 5'-ectonucleotidase, and by adenosine deaminase. On the other hand, dipyridamole, a nucleoside transporter inhibitor, increased the swelling-induced taurine efflux. Extracellular ATP and adenosine increased taurine efflux by potentiating the effect of hypotonic shock. alphabetaMeADP strongly inhibited the effect of extracellular ATP but not that of adenosine. These results suggest that anion channel activation involves the release of intracellular ATP, which is then degraded to adenosine by specific ectoenzymes. Adenosine then binds to purinergic receptors, causing the activation of the channels. To directly demonstrate ATP efflux, cells were loaded with [3H]AMP, and the release of radiolabeled molecules was analyzed by high performance liquid chromatography. During hypotonic shock, cell supernatants showed the presence of ATP, ADP, and adenosine. alphabetaMeADP inhibited adenosine formation and caused the appearance of AMP. Under hypotonic conditions, elevation of intracellular Ca2+ by ionomycin caused an increase of ATP and adenosine in the extracellular solution. Our results demonstrate that volume-sensitive anion channels are regulated with an autocrine mechanism involving swelling-induced ATP release and then hydrolysis to adenosine.

Adenine Nucleotides↗
PubMed1999

N-(4-hydroxyphenyl) retinamide is cytotoxic to melanoma cells in vitro through induction of programmed cell death.

Melanoma is a highly malignant and increasingly common tumour. Since metastatic melanoma remains incurable, new treatment approaches are needed. Previously, we reported that the synthetic retinoid N-(4-hydroxyphenyl)retinamide (fenretinide, HPR) induces apoptosis in neuroblastoma cells, sharing a neuroectodermal origin with melanoma cells. Since no data exist thus far on the effects of HPR on human melanoma tumours, our purpose was to investigate the in vitro modulation of cell growth and apoptosis by HPR in melanoma cells. Ten human melanoma cell lines were exposed in vitro to increasing concentrations of HPR. Dose-dependent growth inhibition and cytotoxicity were observed. According to cytofluorimetric analysis, propidium iodide staining and TUNEL assay, HPR-treated melanoma cells were shown to undergo apoptosis. However, IC50 values ranged from 5 to 28 microM, while IC90 values were between 10 and 45 microM. These last concentrations are approximately 10-fold higher than those achievable in patients given oral HPR. To explore the potential of new delivery strategies, HPR was loaded at high concentrations into immunoliposomes directed to disialoganglioside GD2, a tumour-specific antigen extensively expressed by neuroectoderma-derived tumours. Treatment of melanoma cells for a short time (2 hr) with HPR-containing immunoliposomes followed by culture in drug-free medium gave rise to apoptosis of target cells, whereas cells treated for 2 hr with equivalent concentrations of the free drug survived. The efficacy of immunoliposomal HPR was strongly dependent on the density of GD2 expression in the different cell lines.

Antibody Specificity↗
PubMed1999

GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide.

Melanoma is a highly malignant and increasingly common neoplasm. Because metastatic melanoma remains incurable, new treatment approaches are needed. Immunoliposomes have been previously shown to enhance the selective localization of immunoliposome-entrapped drugs to solid tumors with improvements in the therapeutic index of the drugs. Previously, we reported that the synthetic retinoid fenretinide (HPR) is an inducer of apoptosis in neuroblastoma (NB) cells, sharing the neuroectodermal origin with melanoma cells. HPR is a strong inducer of apoptosis also in melanoma cells, although at doses 10-fold higher than those achievable clinically. Thus, our purpose was to investigate the in vitro potentiation of its cytotoxic effect on melanoma cells in combination with long-circulating GD2-targeted immunoliposomes. GD2 is a disialoganglioside extensively expressed on tumors of neuroectodermal origin, including melanoma. Murine anti-GD2 antibody (Ab) 14.G2a and its human/mouse chimeric variant ch14.18 have been ligated to sterically stabilized liposomes by covalent coupling of Ab to the polyethylene glycol (PEG) terminus. Ab-bearing liposomes showed specific, competitive binding to and uptake by various melanoma cell lines compared with liposomes bearing non-specific isotype-matched Abs or Ab-free liposomes. Cytotoxicity was evaluated after 2 hr treatment, followed by extensive washing and 72 hr incubation. This treatment protocol was designed to minimize non-specific adsorption of liposomes to the cells, while allowing for maximum Ab-mediated binding. When melanoma cells were incubated with 30 microM HPR entrapped in anti-GD2 liposomes, a significant reduction in cellular growth was observed compared to free HPR, entrapped HPR in Ab-free liposomes or empty liposomes. Cytotoxicity was not evident in tumor cell lines of other origins that did not express GD2. Growth of NB cells was also inhibited by immunoliposomes with entrapped HPR.

Antibody Specificity↗
PubMed1999

N-(4-hydroxyphenyl) retinamide inhibits cystogenesis by polycystic epithelial cell lines in vitro.

Primary tubular epithelial cells develop spherical monolayered cysts when cultured in collagenI matrix, a model that has been used to study the mechanism of cystogenesis. In an attempt to block cystogenesis, we have evaluated the effect of N-(4-hydroxyphenyl) retinamide (HPR), a synthetic derivative of retinoic acid, on both formation and growth of cysts in a human model of polycystic kidney cells. Number, dimension and submicroscopical characteristics of cysts were evaluated after 2 and 4 weeks from treatment with HPR. A marked inhibitory effect of HPR on cystogenesis was found at concentration of 1 microM, while a complete block was observed at concentration between 5 and 10 microM. Furthermore, treatment with HPR of already formed cysts resulted in their disruption. HPR at 10 microM also induced apoptosis of several tubular epithelial cell models suggesting a correlation between the two phenomena. Taken together these observations demonstrate that HPR blocks cystogenesis by polycystic kidney cells "in vitro" and that it also reverts the fate of already formed cysts. Apoptosis may be the mechanism which mediates the inhibitory effect on cystogenesis in this model.

Animals↗
PubMed1999

Therapeutic management of stage I-II high-grade primary gastric lymphomas.

The best treatment for primary gastric lymphomas (PGL) has not yet been defined. Eighty-three patients with stage I/II PGL are documented, focusing on prognostic factors, treatment-related morbidity and mortality, and therapeutic outcome. Chemotherapy improved survival in comparison to local treatments, i.e. gastrectomy (n = 15) or gastrectomy and radiotherapy (n = 5). Patients treated with primary chemotherapy and/or radiotherapy (n = 21), with gastrectomy and chemotherapy (n = 26) or with gastrectomy and chemotherapy and radiotherapy (n = 16) showed a similar survival rate. Conservative treatment obtained a 5-year actuarial survival of 82% with a stomach preservation rate of 100%. Two treatment failures and 19 relapses (24%) were observed. Sixty patients (72%) are alive (59 no evidence of disease) at a median follow-up of 58 months. Ten-year actuarial survival is 64%. Local control was influenced by stage, tumor size, depth of infiltration, LDH ratio, and therapeutic modality, while age, stage, LDH ratio, and the use of chemotherapy had independent prognostic value. Because of its efficacy and safety, conservative strategy should be considered as first-line treatment for high-grade PGL. Gastrectomy should be indicated only for urgent cases, in which surgery followed by chemotherapy appears the best choice, followed by radiotherapy in patients with stage II2 disease.

Adult↗
PubMed1999

Non-surgical treatment with primary chemotherapy, with or without radiation therapy, of stage I-II high-grade gastric lymphoma.

Morbidity, mortality and discomfort related to gastrectomy has led some investigators to treat patients with stage I-II primary gastric high-grade lymphoma (PGL) with a conservative strategy. Here we report a retrospective series of 21 patients with PGL treated with primary chemotherapy alone or followed by radiation therapy and analyze previously reported series, focusing on therapeutic results, treatment-related morbidity and stomach preservation rate. All 21 patients with stage I-II PGL received an initial anthracycline-containing chemotherapy, which was followed by involved field-radiation therapy in 8 cases. Data regarding toxicity, response and relapse rates and survival of this patient group and 14 previously published series, involving 316 patients treated with conservative modality, were also analyzed. In the present series two patients did not complete the planned treatment, while the remaining 19 achieved a complete remission (response rate: 90%). Three patients relapsed, all of whom had been treated with chemotherapy alone. Two patients died of lymphoma, one of sepsis and the other of lung cancer while still relapse-free. The survival rate at 50 months is 81%, and the 5-year actuarial cause-specific survival is 82%. The stomach preservation rate is 100%. Previously reported series showed a response rate ranged between 76% and 100%. Gastrointestinal bleeding was observed in only 3% of cases, while no cases of gastric perforation were reported. Treatment mortality rate was 2.5%. 5-year actuarial survival ranged between 73% and 90% and stomach preservation rate was 97%. Short-term chemotherapy obtained similar results to more prolonged treatment. In conclusion, conservative treatment with primary chemotherapy followed by involved field-radiation therapy should be used for the first-line treatment of patients with stage I/II PGL considering that it is associated with a high response and survival rates, and with an insignificant risk of bleeding or perforation, high stomach preservation rate and good quality of life.

Adult↗
PubMed1998

Human neuroblastoma cells produce extracellular matrix-degrading enzymes, induce endothelial cell proliferation and are angiogenic in vivo.

Direct experimental evidence shows that tumor growth and metastases are angiogenesis-dependent. Neuroblastoma (NB) is the most common extracranial malignant solid tumor of childhood. In this study, we investigated 2 human NB cell lines, LAN-5 and GI-LI-N, for their capacity to secrete 2 extracellular matrix-degrading enzymes, MMP-2 and MMP-9, and to induce in vitro human microvascular endothelial cells (EC) to proliferate and in vivo angiogenesis in the chick embryo chorio-allantoic membrane (CAM) assay. Conditioned medium (CM) from both cell lines stimulated in vitro EC proliferation and the effect of LAN-5 CM was higher than that of GI-LI-N cells. Moreover, anti-VEGF, but not anti-FGF2 antibodies, prevented growth increment of EC. NB cell lines secreted the active form of MMP-2 almost exclusively, LAN-5 cells more than GI-LI-N cells. Both cell lines, LAN-5 cells more than GI-LI-N ones, induced angiogenesis in the CAM assay. Our data suggest that the 2 NB cell lines are angiogenic, to LAN-5 cells more than GI-LI-N ones. LAN-5 cells are indeed endowed with a more aggressive and invasive phenotype.

Allantois↗
PubMed1998

Low sensitivity of computed tomography in the staging of gastric lymphomas of mucosa-associated lymphoid tissue: impact on prospective trials and ordinary clinical practice.

The natural history and management of gastric lymphomas of mucosa-associated lymphoid tissue (MALTomas) are not completely understood. Most stage I cases are now entered into prospective trials to confirm the excellent results obtained with conservative treatment, whereas current therapeutic policies are based on accumulated experience. The limits of staging work-ups may have a significant impact on prospective trials and ordinary clinical practice. The authors explore the sensitivity of computed tomography scanning in detecting perigastric adenopathy in 20 patients with gastric MALToma treated by gastrectomy. Clinical staging identified 17 patients as having stage I MALTomas and three patients as having stage II1 MALTomas. Histopathologic staging showed that 8 of 17 patients formerly diagnosed with stage I MALToma had perigastric nodal involvement, whereas the three patients with clinical stage II1 were confirmed as such. Computed tomography scanning has low sensitivity in detecting perigastric lymphadenopathy in gastric MALTomas. This leads to understaging, with a significant impact on therapeutic decision, and distorts newly acquired knowledge about the disease's natural history and management, introducing a bias in prospective clinical trials. Endoscopic ultrasonography should be tested as a staging procedure both in prospective trials and in ordinary clinical practice.

Adolescent↗
PubMed1998

Erythrocytosis in a patient with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) can be accompanied by compensatory secondary erythrocytosis. However, the exact prevalence of secondary erythrocytosis in COPD is unknown. Although diagnostic criteria for polycythemia vera versus secondary erythrocytosis are mutually exclusive, we describe here the coexistence of polycythemia vera and COPD in the same patient.

Aged↗
PubMed1997

Primary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic management.

BACKGROUND: Primary cardiac lymphoma (PCL) is extremely rare in immunocompetent patients. Different definition criteria have been employed in published series. Prognosis is poor due to diagnostic delay and relevance of the site of disease. METHODS: Two cases observed at the study institution are reported, with a review of 48 cases published in the literature from 1980 to 1996. Only patients with lymphoma confined to the heart and/or pericardium and those with a single and asymptomatic extracardiac site were considered for analysis. RESULTS: Eight patients had minimal extracardiac disease. The most common presentation was unresponsive heart failure. Electrocardiography findings were not specific. PCL usually arose in the right chambers as a mass, with or without pericardial effusion (> 80%). Chest X-rays, transthoracic echocardiography, and computed tomography scans are standard in diagnostic workup, but transesophageal echocardiography (TEE) and magnetic resonance imaging (MRI) showed a sensitivity > 90%. Cytology of pericardial effusion was diagnostic in 67% of cases. Thoracotomy was diagnostic in all cases, whereas less invasive procedures had high false-negative rates. Gross resection has no role. Early anthracycline-containing chemotherapy appears to improve survival, whereas the role of radiotherapy has not yet been defined. CONCLUSIONS: The diagnosis of PCL should be considered in patients with a cardiac mass and/or unexplained refractory pericardial effusion. Adequate diagnostic workup, including TEE and MRI, allows confirmation of the early suspicion of PCL. In the absence of a diagnostic cytology, an open biopsy may be indicated to avoid treatment delay. There is no evidence that PCL should be treated differently from other bulky aggressive lymphomas arising at other anatomic sites.

Adolescent↗
PubMed1997

HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia.

In allogeneic bone marrow transplantation (allo-BMT), donor lymphocytes play a central therapeutic role in both graft-versus-leukemia (GvL) and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GvHD). Eight patients who relapsed or developed Epstein-Barr virus-induced lymphoma after T cell-depleted BMT were then treated with donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. The transduced lymphocytes survived for up to 12 months, resulting in antitumor activity in five patients. Three patients developed GvHD, which could be effectively controlled by ganciclovir-induced elimination of the transduced cells. These data show that genetic manipulation of donor lymphocytes may increase the efficacy and safety of allo-BMT and expand its application to a larger number of patients.

Bone Marrow Transplantation↗