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Biomedical subjects

M Coscia

Publications and source records attributed to M Coscia.

At least 19 recordsLinked to original sources
PubMed2005

Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma.

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta T cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gammadelta T cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.

Antineoplastic Agents↗
PubMed2004

Long-term follow-up of idiotype vaccination in human myeloma as a maintenance therapy after high-dose chemotherapy.

The aim of this work was to evaluate the long-term immunological and clinical impact of idiotype (Id) vaccination in multiple myeloma (MM) patients in first remission after high-dose chemotherapy. A total of 15 patients received a series of subcutaneous (s.c.) injections of autologous Id, conjugated to keyhole limpet hemocyanin (KLH) and in association with low doses of GM-CSF. The median duration of follow-up was 110 months from diagnosis. The vaccine induced immune responses that lasted almost 2 years after the end of treatment. Antibody responses included anti-KLH IgM and IgG (90% of patients), anti-KLH IgE (30%), anti-GM-CSF IgG (20%), anti-Id IgG (20%), and anti-Id IgE (30%). Id-specific delayed type hypersensitivity skin tests were positive in 85% of tested patients. Following vaccination, a progressive recovery of T-cell receptor (TCR) diversity was observed and the loss of oligoclonality was significantly correlated with the remission duration. Although Id/KLH conjugates did not eliminate the residual tumor burden, the median progression-free survival, and overall survival were 40 and 82 months, respectively. A retrospective case-matched analysis showed similar results in patients treated with IFN-alpha alone or in association with steroids. This vaccine formulation can overcome Id-specific immune tolerance by inducing clinical responses that are worthy of further investigation.

Adjuvants, Immunologic↗
PubMed2001

Severe and long-lasting disruption of T-cell receptor diversity in human myeloma after high-dose chemotherapy and autologous peripheral blood progenitor cell infusion.

Vaccine-based strategies are currently under investigation as a means of inducing tumour-specific immune responses and improving the clinical outcome of multiple myeloma (MM) patients in remission after high-dose chemotherapy and peripheral blood progenitor cell (PBPC) infusion. The immune competence of these patients was investigated by determining the overall diversity of the T-cell receptor (TCR) repertoire in the peripheral blood (PB) and bone marrow (BM). The average time after transplantation was 13 months. The clonality and reciprocal usage of BV gene segments (TCRBV repertoire) was estimated at the cDNA level and membrane protein expression. The TCRBV repertoire of MM was severely disrupted compared with age-matched normal donors. On average, one-third of the total repertoire in both the PB and the BM consisted of T cells expressing oligoclonal TCRbeta transcripts. Flow cytometry showed an increased frequency of abnormally expanded BV subfamilies at both sites. BV expansions were predominantly CD8+ and had the phenotype of antigen-experienced memory T cells as well as T cells with the naive phenotype. Oligoclonality was not restricted to phenotypically expanded BV subfamilies, but also involved normally represented BV subfamilies. The TCR repertoire of MM in remission was then compared with monoclonal gammopathy of undetermined significance (MGUS) and MM patients at diagnosis. The degree of TCR diversity was similar in age-matched normal donors and MGUS, but progressively decreased from MGUS to MM at diagnosis and then to MM in remission. These data indicate that: (1) there is a long-lasting and severe disruption of TCR diversity after high-dose chemotherapy and PBPC infusion, and (2) the extent of TCR disruption may affect the clinical outcome of vaccine-based strategies delivered at the stage of minimal residual disease.

Bone Marrow Cells↗
PubMed2000

Increased expression of non-functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients.

Different MHC class I-specific killer inhibitory receptors (KIRs) are expressed in vivo by a minor fraction of activated memory CD8+ cells. It has been postulated that KIRs may 'fine-tune' specific responses by altering their threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells (CD38+, HLA-DR+, CD25-, CD45R0+, CD28-). We investigated the expression of KIRs on MM T cells and determined their possible influence on cytolytic responses elicited via the CD3-TCR complex. The expression of CD94, a molecule that is part of a heterodimeric KIR recognizing the non-classical MHC surface HLA-E molecule, was almost threefold higher in MM T cells than in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8+ cells but not restricted to activated (HLA-DR+) and/or memory (CD45R0+) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94+ MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively. CD94 blockade did not significantly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T cells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8+ cells do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impaired.

Antibodies, Monoclonal↗
PubMed1999

Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy.

Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Adjuvants, Immunologic↗
PubMed1994

Acute cauda equina syndrome. Diagnostic advantage of MRI.

Speed and completeness are vital in the radiographic evaluation of an acute cauda equina syndrome presentation to maximize its resolution with rapid appropriate surgical intervention. Magnetic resonance imaging provides the optimal method for non-invasive evaluation.

Acute Disease↗
PubMed1991

Direct anterior fixation of dens fractures with a cannulated screw system.

Anterior screw fixation of dens fractures appears to be an optimal method of treatment for these injuries. Anatomic dens fracture reduction with stable internal screw fixation satisfies the established principles of the AO/ASIF. Iatrogenic trauma is minimized by the use of an anterior surgical approach, and no supplemental bone grafting is required. This procedure is quite prone to complications when performed improperly or in contraindicated situations. The use of meticulous surgical technique along with a newly designed cannulated screw system has evolved this procedure into an established form of treatment at our department. Since 1982, 23 patients were treated with direct screw fixation of dens fractures. The overall rate of fracture union was 92.3%, and fracture resolution averaged 5.5 months. The major complication rate of 17% (4/23) resulted from inappropriate use of this technique. The 11 most recent cases, all of which involved stabilization with cannulated screws, resulted in only a single complication (9%) and an average fracture healing time of 3.5 months. A recommended operative technique for anterior screw fixation of dens fractures will be presented along with a discussion of potential sources of difficulty or failures.

Bone Screws↗
PubMed1989

Fractures of the odontoid process. Treatment with anterior screw fixation.

Seventeen cases of Anderson and D'Alonzo Type II and "shallow" Type III fractures of the odontoid, treated by anterior screw fixation, were reviewed and compared with previously published series of fractures treated nonoperatively, treated with posterior C1-C2 arthrodeses, and with anterior screw fixation series. Although the nonunion rate (12%) and major complication rate (24%) in the present series were higher than those previously reported, the combined rates of all anterior screw fixation series were comparable to those of posterior C1-C2 arthrodesis studies. Three of the complications presented occurred in cases that in retrospect were inappropriate for the use of this technique. These included a verified nonunion and 2 individuals with markedly osteoporotic bone and unfavorable fracture type. Because of the difficulty involved in mastering anterior screw fixation of the dens, its use should be limited to experienced spine surgeons with the appropriate surgical facilities.

Axis, Cervical Vertebra↗
PubMed1989

[Bone screw osteosynthesis of dens fractures. Technical surgical aspects and results].

Twenty cases of Anderson and d'Alonzo type II and "shallow" type III fractures of the dens were treated by anterior screw fixation: the results were reviewed and compared with previously published results obtained in series of such fractures treated non-surgically, by posterior C1-C2 arthrodesis or anterior screw fixation. The complication rate of 25% in our series is comparable to those reported in a previously published review of studies on posterior wiring for C1-C2 arthrodesis. Three of our cases in which complications occurred (15%) were recognized in retrospect as inappropriate for the use of this technique: in one of these patients there was confirmed non-union, and the other two had markedly osteoporotic bone. A meticulous operative technique and the use of special instruments may improve the success rate. The anterior screw fixation method, however, allows for maximal post-treatment cervical motion, since it makes arthrodesis unnecessary and minimizes the degree and duration of postoperative external immobilization. It also reduces the iatrogenic trauma since an anterior rather than a posterior cervical approach is taken and supplementary bone grafting is not required. Anterior screw fixation of type II dens fractures appears to be the ideal method of treatment for these injuries, but since it is difficult to perform its use should be limited only to experienced spine surgeons with access to the appropriate surgical facilities.

Adolescent↗
PubMed1988

Infection-related spontaneous atlantoaxial dislocation in an adult. Case report.

This paper reports the third described case of infection-related atlantoaxial subluxation in an adult. Like most of the similar cases seen in the pediatric literature, this case was associated with a parapharyngeal beta-hemolytic streptococcal abscess. Based upon this experience, the authors advocate intravenous antibiotic therapy and 1) immediate reduction followed by application of a halo brace; 2) immobilization in a halo brace for at least 3 months; and 3) a C1-2 wiring and fusion procedure for patients who fail this trial of conservative therapy.

Abscess↗
PubMed1977

Ectopic production of antidiuretic hormone (adh), adrenocorticotrophic hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) by an oat cell carcinoma of the lung.

A 61 year old woman presented with profound hyponatremia and markedly low serum osmolality. Urine osmolality was greater than the serum osmolality, an abnormality that was corrected by water restriction, suggesting inappropriate ADH secretion. Although there were no physical signs of Cushing's syndrome, her serum potassium level was low and markedly elevated levels of plasma and urine corticosteroids were not altered by the administration of large amounts of dexamethasone, suggesting the ectopic ACTH-MSH syndrome. Plasma levels of immunoreactive ACTH and beta-MSH were elevated. At autopsy, a metastastic oat cell carcinoma of the lung, not detected antemortem by chest roentgenograms and bronchoscopy, was found. Immunoreactive ADH, ACTH and beta-MSH were detected in the primary tumor and in metastases to the liver. beta-MSH was also detected in the spleen, in which metastases were observed. This is the first documented case of the simultaneous production of ADH, ACTH and beta-MSH by neoplastic tissue associated with clinical manifestations of the syndrome of inappropriate ADH secretion and the ectopic ACTH-MSH syndrome.

Adrenocorticotropic Hormone↗