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Biomedical subjects

A Mazzoni

Publications and source records attributed to A Mazzoni.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mobilization, collection, and characterization of peripheral blood hemopoietic progenitors after chemotherapy with epirubicin, paclitaxel, and granulocyte-colony stimulating factor administered to patients with metastatic breast carcinoma.

BACKGROUND: As single agents, both paclitaxel and epirubicin in combination with cytokines can mobilize peripheral blood progenitor cells (PBPCs). The authors have demonstrated previously that the combination of epirubicin and paclitaxel is very active against metastatic breast carcinoma and tolerated by patients. METHODS: Twenty-one patients with metastatic breast carcinoma received epirubicin 90 mg/m2 in combination with paclitaxel 200 mg/m2 given as a 3-hour infusion, and granulocyte-colony stimulating factor (G-CSF) starting 24 hours after chemotherapy to mobilize PBPCs. An immunophenotypic analysis for CD3, CD4, CD8, CD 19, CD33, CD34, and CD38 antigen expression was performed on apheresis products. Eighteen patients underwent high dose chemotherapy and were engrafted with PBPCs primed with paclitaxel, epirubicin, and G-CSF. RESULTS: The median number of circulating CD34+ cells at peak was 70/microL; in the patients less heavily pretreated, it was 106.7/microL. The mean number of CD34+, CD34+/CD33-, and CD34+/CD38- cells/kg collected per apheresis was 6.3 x 10(6), 2.0 x 10(6), and 0.18 x 10(6), respectively. The mean number of CD34+ cells/kg per apheresis was 7.8 x 10(6) when the preleukapheresis CD34+ cell count was more than 50/microL and 0.9 x 10(6) when the CD34+ cell count was less than 50/microL. The mean number of CD3+, CD4+, and CD8+ cells/kg collected per apheresis was 90 x 10(6), 50 x 10(6), and 30 x 10(6), respectively. CONCLUSIONS: Epirubicin plus paclitaxel in combination with G-CSF mobilizes PBPCs, including more primitive progenitors capable of supporting myeloablative treatment. Moreover, the mononuclear cells collected in this study contained high levels of cytotoxic effector cells suitable for ex vivo manipulation to augment the antitumor effect.

Adenocarcinoma↗
PubMed1998

AIDS-related visceral aspergillosis: an underdiagnosed disease during life?

Five out of nine consecutive patients with HIV-related visceral aspergillosis observed by us since 1984 were diagnosed only at necropsy examination. The histopathological features of these five patients [two with isolated pneumonia, one with central nervous system (CNS) involvement, one with brain abscess and respiratory disease and one with pulmonary, pleural and kidney infection] have been evaluated according to epidemiological, clinical and radiological features. On the basis of our experience, life-threatening aspergillosis, which is often misdiagnosed or missed in the setting of HIV infection and AIDS, should be suspected in patients with far-advanced underlying disease and unexplained signs and symptoms, even in the absence of some presumed risk factors (i.e. neutropenia and prior steroid treatment). Plain chest radiography and bronchoscopy with broncholaveolar lavage may fail to reveal respiratory disease, CNS aspergillosis is not necessarily associated with suggestive neuroradiological features and disseminated disease may present with multiorgan failure. The unfavorable outcome of this emerging AIDS complication can be improved only by earlier diagnosis based on invasive techniques and appropriate and timely treatment.

AIDS-Related Opportunistic Infections↗
PubMed1998

A nosocomial cluster of Candida inconspicua infections in patients with hematological malignancies.

Candida inconspicua was recovered from three patients with hematological malignancies. Two patients had intravenous-catheter-associated fungemia, whereas the third had fungal hepatitis. The three cases of infection occurred over a period of 1 month in patients staying in adjacent single rooms. In vitro susceptibility testing of fungal strains showed all isolates to be resistant to fluconazole, with MICs greater than 32 microg/ml. All of the strains had identical DNA restriction profiles and randomly amplified polymorphic DNA fingerprints. These data suggest a nosocomially acquired infection emanating from a common source within the hospital environment.

Adult↗
PubMed1998

The system of the modified transcochlear approach: a lateral avenue to the central skull base.

OBJECTIVE: This study aimed to update the authors' experience with the modified transcochlear approach for the management of lesions of the central skull base. The surgical technique, classification, indications, and results also are presented. STUDY DESIGN: A retrospective review of the charts of 66 consecutive patients treated in our centers by the modified transcochlear approach was conducted. SETTING: The study was performed in two tertiary referral centers. PATIENTS: All patients treated by the modified transcochlear approach were included. Thirty-five patients had extradural lesions, whereas 31 lesions were intradural. INTERVENTION: All patients were treated surgically using the modified transcochlear approach either in its basic form (type A) or with its extensions (types B, C, and D). MAIN OUTCOME MEASURES: The outcome of surgery is evaluated with particular emphasis on the incidence of morbidity, mortality, and the degree of total tumor removal. RESULTS: Total tumor removal was accomplished in 58 cases either in single or staged procedures. A second-stage procedure for total tumor removal is planned in five other patients. Subtotal tumor removal was performed in three patients. Mortality occurred in two cases. Ipsilateral hearing loss and immediate facial nerve palsy constituted the major drawbacks of this approach. However, 67.5% recovered to grade III facial function or better 1 year after surgery. CONCLUSIONS: The modified transcochlear approach provides a relatively safe, wide, and versatile access to large lesions of the central skull base.

Adolescent↗
PubMed1997

Efficiency of T cell triggering by anti-CD3 monoclonal antibodies (mAb) with potential usefulness in bispecific mAb generation.

T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti-CD3/anti-tumor cells (bs-mAbs). Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity, but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti-CD3 mAbs recognized the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did alpha CD3 (the bivalent anti-CD3 mAb produced by the hybrid hybridoma OC/TR). TR66 and OKT3, as determined by measurement of the affinity constants. In all lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas alpha CD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells. Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical application.

Antibodies, Bispecific↗
PubMed1997

Reciprocal association between insulin sensitivity and the haematocrit in man.

In epidemiological studies, a high haematocrit has been associated both with increased cardiovascular risk and with hyperinsulinaemia, a surrogate of insulin resistance. To examine directly the relationship between the haematocrit and insulin sensitivity, we studied 12 healthy volunteers and 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) with the use of a 4-hour hyperinsulinaemic [1 mU min-1 kg-1] isoglycaemic clamp. In the whole group, insulin sensitivity (as the ratio of insulin-mediated glucose clearance to steady-state plasma insulin concentrations) was inversely related to the haematocrit (r = 0.50, P < 0.01). To test whether acute changes in the haematocrit affect insulin sensitivity, in two NIDDM patients and three healthy subjects the clamp study was repeated after lowering (-18%) the haematocrit by erythro-apheresis. In all five subjects, the lower haematocrit was associated with slightly reduced (-7% on average, P = NS) rather than increased insulin sensitivity. We conclude that insulin sensitivity is inversely related to the haematocrit independently of the glucose tolerance status. The association does not result from acute haemodynamic effects on insulin sensitivity, and may therefore reflect an action of insulin resistance/ hyperinsulinaemia on blood viscosity, or the presence of a common determinant.

Adult↗
PubMed1997

Lower cranial nerve schwannomas involving the jugular foramen.

Schwannomas involving the jugular foramen are rare lesions, and no consensus exists on their management. This paper reports on 20 such cases treated in our centers. Nineteen cases were operated on for removal of the tumors, and the remaining case is being managed by watchful expectancy. Fifteen cases were operated on by the petro-occipital trans-sigmoid approach with or without labyrinthectomy, 2 by the infratemporal fossa approach, 1 by the modified transcochlear approach, and 1 by the jugulo-petrosectomy approach. The petro-occipital trans-sigmoid approach allowed single-stage, total tumor removal with preservation of the facial nerve and of middle and inner ear functions. Lower cranial nerve paralysis was the major complication and seemed to be inherent to the disease rather than to the approach used. No cerebrospinal fluid leak or meningitis occurred in the present series. So far, no recurrence has been detected.

Adult↗
PubMed1996

CD3-CD28 costimulation as a means to avoiding T cell preactivation in bispecific monoclonal antibody-based treatment of ovarian carcinoma.

One of the major limitations to the immunotherapy of ovarian carcinoma based on the use of anti-CD3/antitumor bispecific monoclonal antibodies (bi-mAb) is the need for preactivation of effector cells ex vivo, because cross-linking of the T cell receptor-CD3 complex per se may lead to T-cell unresponsiveness or even apoptosis. The bi-mAb OC/TR, which recognizes the folate-binding protein (FBP) overexpressed in 90% of ovarian carcinomas and the CD3 molecule on T cells, has demonstrated efficacy in a clinical setting. Here we investigated the possibility of delivering accessory signals to OC/TR-retargeted peripheral blood mononuclear cells (PBMCs) via an anti-CD28 mAb or an anti-FBP/anti-CD28 bi-mAb. Coculture of resting PBMCs from healthy donors with OC/TR, anti-FBP/anti-CD28 bi-mAb, and FBP+ tumor cell lines resulted in a highly activated phenotype of effector cells and in a dramatic in vitro growth inhibition of the target cells without an increase in OC/TR-redirected lysis. Whereas both the CD4 and CD8 T cell subsets were involved in the growth inhibition, only the CD8 subpopulation accounted for the cytotoxic activity. The in vitro tumor growth inhibition was mediated mainly by soluble factors, which were active on both FBP+ and FBP- ("bystander effect") cell lines. Activation and antitumor activity were also observed, albeit to a lesser extent, using OC/TR and monospecific bivalent anti-CD28 mAb. In vitro analysis demonstrated that cross-linking between tumor and effector cells for at least 24 h was needed to achieve T-cell activation and development of antitumor activities. Thus, ex vivo CD3-CD28 costimulation on resting PBMCs might be of therapeutic utility for local treatment of minimal residual disease.

Antibodies, Bispecific↗
PubMed1996

Further characterization of cytotoxic T cells generated by short-term culture of human peripheral blood lymphocytes with interleukin-2 and anti-CD3 mAb.

In this study we have specifically investigated the participation of T cells in the cytotoxic activity of peripheral blood lymphocytes (PBL) activated by interleukin-2 (IL-2, 50 U/ml) alone or in combination with an anti-CD3 mAb (BMA030, 10 ng/ml, IgG2a). Purified CD3+ T cells, incubated in the presence of the anti-CD3 mAb for 4 days, mediated a cytotoxic activity against HL60 and U937 tumor cell lines. Several findings suggested the involvement of a redirected-cytotoxicity phenomenon, since the lytic process was restricted to target cell lines bearing the high-affinity Fc gamma receptor (Fc gamma RI) and T lymphocytes stimulated by IL-2 alone did not lyse these cell lines. Furthermore, anti-CD3 mAb F(ab')2, anti-CD3 IgG1 (UCHT1), phytohemagglutinin or staphylococcal enterotoxin A did not induce a similar cytotoxic activity in T lymphocytes. The cytotoxic process occurred in the presence of a very low level of anti-CD3 antibodies (in the nanomolar range). The cytotoxic activity of T cells stimulated by IL-2 or by IL-2 + BMA030, against OVCAR-3 cells (MOv18+ ovarian tumor cell line), was also compared in the presence of a bispecific antibody OC/TR, anti-CD3 x MOv18). The stimulation by IL-2 + BMA030 induced approximately a twofold higher cytotoxic activity than IL-2-activated T cells. This could be related to the state of activation of effector cells stimulated by IL-2 + BMA030, since the phenotypic analysis showed an increased proportion of T cells expressing several activation/differentiation markers (CD25, HLA-DR, CD45R0, adhesion molecules). These findings could be applied to the design of therapeutic protocols using anti-CD3 x antitumoral bispecific antibodies.

Antibodies, Bispecific↗
PubMed1996

The system of the modified transcochlear approaches to the petroclival area and the prepontine cistern.

Between June 1986 and June 1993 46 different tumors (27 extradural and 19 intradural) located in the petroclival area and/or prepontine cistern have been operated on at The Gruppo Otologico Piacenza and the ENT Department of Bergamo, Italy using a modification of the transcochlear approach. Total tumor removal was obtained in all cases. Complications occurred in eight patients. One patient died due to infarction of the brain stem. The system of modified transcochlear approaches conceived for the removal of various intradural and extradural tumors is presented. This approach, together with its modifications, is the major operative access to the central skull base and clivus among a series of lateral approaches described in the literature. The basilar surgical technique (type A) and its modifications (types B, C, D) are described in detail, and five different, illustrative cases are presented. Indications, limits, results, and complications related to the approach are discussed.

Journal Article↗
PubMed1996

Residual and recurrent acoustic neuroma in hearing preservation procedures: neuroradiologic and surgical findings.

Magnetic resonance imaging with gadolinium DTPA is currently the most accurate method for detecting small intracanalicular yestibular schwannomas. This imaging modality is not nearly as clear in diagnosis of a small residual or recurrent neuroma after a hearing preservation procedure. This study looked for gadolinium-enhanced MRI images mimicking recurrent lesions in 104 consecutive cases of unilateral acoustic neuroma removed with a hearing preservation technique by the retrosigmoid transmeatal approach. A number of cases with enhancing MRI images in the internal anditory canal were reoperated, permitting the histologic examination of the enhancing tissue. Criteria for the MRI diagnosis of residual-recurrent acoustic neuroma are presented, along with the short-to mid-term rate of "residual-recurrent" tumor.

Journal Article↗
PubMed1996

Morphologic features and clinical significance of skin involvement in patients with AIDS-related cryptococcosis.

Eight out of 30 consecutive patients with AIDS and cryptococcal meningoencephalitis (26,7%) presented cutaneous involvement, in the form of papulo-nodular lesions in 3 patients, molluscum contagiosum-like lesions in 3 patients, and pustular-ulcerative lesions in 2 patients. Skin localization represented an untoward prognostic sign, and in 3 out of 8 patients the lesions were diagnosed 2 to 6 weeks before the onset of systemic and neurologic signs and symptoms of the disease. A systematical examination of all suspected cutaneous lesions in subjects with advanced HIV disease may lead to an earlier diagnosis and treatment of disseminated cryptococcosis.

AIDS-Related Opportunistic Infections↗
PubMed1995

Anti-tumor efficacy of an anti-epidermal-growth-factor-receptor monoclonal antibody and its F(ab')2 fragment against high- and low-EGFR-expressing carcinomas in nude mice.

Monoclonal antibody (MAb) MINT5 specifically detects the epidermal-growth-factor receptor (EGFR). In vitro analyses of intact MINT5 (IgG1) and its F(ab')2 fragment indicated that both forms of the MAb inhibited binding of 125I-mEGF to EGFR, induced receptor internalization and blocked EGF-induced EGFR tyrosine-kinase activation in A431 cells. Both forms of the MAb also inhibited to the same extent the proliferation of the carcinoma cell lines A431 and IGROVI, despite the difference in EGFR levels on the cells. The detection of TGF alpha mRNA and the inhibition of cell growth in EGF-free conditions by anti-EGFR MAb indicated the involvement of an EGFR/TGF alpha autocrine/paracrine pathway in the in vitro growth of both cell lines. Analysis of mice xenotransplanted s.c. with A431 cells and treated with MINT5 revealed a block in A431 tumor take in 6 of 10 animals when intact MAb was administered from day 0 to day 11. On a molar basis, F(ab')2 at the same dose was ineffective, although at a 7-fold higher dose F(ab')2 reduced s.c. tumor growth by 80%. At the same dose, intact MINT5 MAb reduced s.c. growth of the EGFR-negative MeWo cell line by 5%. Survival of mice bearing IGROVI i.p. xenotransplants and treated locally with either form of MAb was significantly prolonged even when treatment was initiated on day 3. Corrected doses of intact and F(ab')2 fragment, which accounted for the difference in serum half-lives of the MAb forms, resulted in similar survival rates in the tumor-bearing mice. These pre-clinical results suggest that MINT5 MAb might be safely used for systemic therapy of EGFR-over-expressing tumors. Loco-regional therapy might be contemplated in the case of tumors with moderate/low EGFR expression.

Animals↗
PubMed1995

"Atypical" multidrug resistance in human ovarian cancer cell line A2780 selected for resistance to doxorubicin (A2780 DX3).

Human ovarian cancer cells A2780, selected for resistance to doxorubicin (A2780-DX3), are cross-resistant to various other topoisomerase-II-targeted drugs but not to vinblastine. The parental cell line was very sensitive to doxorubicin-, mitoxantrone- or etoposide(VP16)-induced DNA single-strand breaks, under deproteinizing conditions. In contrast, little or no DNA strand breakage was seen in resistant A2780-DX3 cells, even at very high concentrations, indicating a good correlation, with cytotoxicity. No significant alterations in cellular drug uptake were observed in DX3 cells. Further studies showed that the nuclei isolated from resistant cells were also resistant to mitoxantrone- or VP16-induced single-strand breaks, indicating that nuclear modifications in resistant cells are responsible for this resistance. Catalytic activity in crude nuclear extracts from wild-type and DX3 cells was almost equal. However, an assay that specifically measures generation of 5'-protein-linked breaks in 32P-labeled 3 DNA revealed that, DNA cleavage activity in nuclear extract from the DX3 cell line is profoundly resistant to a stimulation by VP16. These data indicate that stimulation of topoisomerase-II-mediated DNA cleavage is responsible for topoisomerase-II-targeted drug-cytotoxicity rather than loss of normal topoisomerase catalytic function. These data support the hypothesis that A2780-DX3 cells display an "atypical" multidrug resistance.

Antineoplastic Agents↗