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Vittorio Perfetti

Publications and source records attributed to Vittorio Perfetti.

15 recordsLinked to original sources
PubMed2006

Therapy and management of systemic AL (primary) amyloidosis.

The optimal treatment of immunoglobulin light chain amyloidosis (AL) patients requires early diagnosis, correct amyloid typing, effective treatment and careful supportive therapy. In the last few years the therapeutic arsenal for the management of AL has been considerably enriched. Cardiac dysfunction can be accurately monitored by measuring the serum concentration of natriuretic peptide type-B and cardiac troponins and the quantitative test for circulating free light chains allows an easy assessment of haematological response to chemotherapy. These new tools can be combined in order to maximise the improvement of organ dysfunction and minimise toxicity, adapting the intervention to each patient.

Amyloidosis↗
PubMed2006

Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL.

N-terminal natriuretic peptide type B (NT-proBNP) is a marker of cardiac dysfunction in light chain amyloidosis (AL) and a powerful prognostic determinant. Serum NT-proBNP and circulating free light chains (FLCs) were measured at enrollment and after 3 cycles of chemotherapy in 51 patients with cardiac AL. In patients (n = 22, 43%) in whom FLCs decreased by more than 50% (hematologic response), NT-proBNP concentration decreased by a median of 48%, whereas in the remaining patients it increased by 47% (P = .01). The reduction of NT-proBNP was greater in patients (n = 9) in whom amyloidogenic FLCs disappeared at immunofixation (median 53%), than in the remaining responding patients (median 31%, P = .04). Left ventricular wall thickness decreased by at least 2 mm in 3 of 20 patients in whom NT-proBNP improved. Fifteen patients died. Thirteen of them, in whom NT-proBNP and FLCs did not improve, died after a median of 1.8 months. The decrease of FLCs translates into a simultaneous decrease of NT-proBNP and improved survival. Patients in whom chemotherapy fails to induce such a decrease are at risk of early death. Cardiac function in AL can rapidly improve due to a reduction of the circulating amyloidogenic precursor, despite the amount of cardiac amyloid deposits remaining apparently unaltered, as measured by echocardiography.

Adult↗
PubMed2006

Unusual manifestations of disseminated neoplasia at presentation: right-sided heart failure due to a massive cardiac metastasis and autoimmune thrombocytopenia in pleomorphic rhabdomyosarcoma of the adult.

Although it is recognized that aggressive soft tissue sarcomas may give rise to cardiac metastases, these manifestations are usually late and clinically silent, being the prevailing finding in exceptional cases. This report describes the occurrence of a massive cardiac metastasis at diagnosis of leg rhabdomyosarcoma in a middle-age adult. This manifestation was the cause of rapidly progressive congestive heart failure and, together with the unusual occurrence of autoimmune thrombocytopenia, led to difficult patient care with a significantly negative influence on the outcome.

Adult↗
PubMed2006

Long-term results of a risk-adapted approach to melphalan conditioning in autologous peripheral blood stem cell transplantation for primary (AL) amyloidosis.

BACKGROUND AND OBJECTIVES: High-dose melphalan with autologous peripheral blood stem cell transplantation (ASCT) is an effective treatment for systemic primary amyloidosis. This procedure is, however, associated with substantial toxicity and mortality, particularly if the heart is involved. Refined selection of patients suitable for transplantation and personalized adaptation of the doses of melphalan might improve the outcome. DESIGN AND METHODS: Twenty-two consecutive patients were selected for age, number of organ systems involved, heart and kidney function, and treated with risk-adapted melphalan conditioning. This was first-line therapy in 81% of cases. RESULTS: Fifty-five percent of the patients had amyloid involvement of two organ systems, with renal involvement predominant in half. Approximately 70% received full-dose melphalan. Toxicity was manageable and three transplant-related deaths (14%) occurred only in the early phase of the study. The median overall survival was 68 months. The intent-to-treat hematologic response rate was 55% at +12 months (complete, 36%; partial, 19%), which was accompanied by organ responses in 75%. Survival was positively influenced by: (i) hematologic response at +3 months (complete+partial responses 55%, median not reached, more than 108 months; no response, median 17 months) (p=0.001); (ii) amyloid involvement of a single organ system (p=0.016). Prolonged follow-up demonstrated that remissions are durable, but relapses may occur as 4 of 12 responsive patients (33%) relapsed, three from complete response, between +30 to +38 months. INTERPRETATION AND CONCLUSIONS: The present risk-adapted approach produced acceptable toxicity and peri-transplant mortality with prolonged survival in responsive patients. Additional therapy should be considered if no hematologic response is observed at +3 months after ASCT.

Adult↗
PubMed2005

Clinical aspects of systemic amyloid diseases.

Amyloidosis is a protein misfolding disorder in which soluble proteins aggregate as insoluble amyloid fibrils. Protein aggregates and amyloid fibrils cause functional and structural organ damage respectively. To date, at least 24 different proteins have been recognized as causative agents of amyloid diseases, localized or systemic. The two most common forms of systemic amyloidosis are light-chain (AL) amyloidosis and reactive AA amyloidosis due to chronic inflammatory diseases. beta(2)-microglobulin amyloidosis is a common complication associated with long-term hemodialysis. Hereditary systemic amyloidoses are a group of autosomal dominant disorders caused by mutations in the genes of several plasma proteins. Heterogeneity in clinical presentation, pattern of amyloid-related organ toxicity and rate of disease progression is observed among systemic amyloidoses. In particular, beta(2)-microglobulin presents unique clinical features compared to the other systemic forms. The phenotypic features of hereditary systemic amyloidoses may instead overlap those of the two more common forms of acquired amyloidoses mentioned above and therefore a correct diagnosis can not rely only on clinical grounds. Unequivocal identification of the deposited protein is essential in order to avoid misdiagnosis and inappropriate treatment. Amyloid deposits can be reabsorbed and organ dysfunction reversed if the concentration of the amyloidogenic protein is reduced or zeroed. At present, the most effective approach to treatment of the systemic amyloidoses involves shutting down, or substantially reducing the synthesis of the amyloid precursor, or, as in the case of beta(2)-microglobulin, promoting its clearance.

Adult↗
PubMed2005

Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogeneous clinical settings.

This study was designed to report the pharmacokinetic behavior of Rituximab in patients affected with different diseases and treated with different schedules of administration. A low tumor burden was a common feature of all patients (N=48) included in our study, whereas the timing of Rituximab administration varied from weekly (groups 1, 2, 3) to monthly (group 4). Group 1 included patients with follicular lymphoma treated with 4 weekly doses of Rituximab after first-line chemotherapy with CHOP. At the start of Rituximab, patients were in partial or complete clinical response but showed persistence of disease at molecular level (bcl-2-positive) in bone marrow and/or peripheral blood. Patients in group 2 had autoimmune disorders and Rituximab was given to act on B-cells, interfering with their production of autoantibodies. In patients with amyloidosis (group 3), Rituximab was given to kill progenitor B-cells of the small clone terminating in amyloid-producing plasma cells. In groups 2 and 3, the target of monoclonal antibody was a population of small B cells, which make an intrinsic feature of the diseases. Group 4 included patients with relapsed or refractory follicular and mantle cell lymphoma who underwent a salvage program of immunochemotherapy, purging in vivo and autotransplant: the first of the six planned doses of Rituximab was administered after a debulking phase with a third-generation regimen, such as VACOP-B. An enzyme-linked immunoassay (ELISA) developed and validated in our laboratory was used for the pharmacokinetic study. Rituximab disposition was characterized by a 2-exponential decay, with a long elimination half-life of approximately 3 weeks (range, 248-859 hours). The total systemic clearance ranged between 3.1 and 11.9 mL/hr/m. After 4 weekly infusions, Rituximab concentration was approximately 2.5 microg/mL, which is approximately 85% of the steady-state level. Steady-state plasma concentrations of Rituximab were reached after 6 to 8 weekly infusions. The adopted pharmacokinetic model (2-compartment open model) seems to provide the best fit of Rituximab disposition both during and after treatment, even when different schedules of drug administration are used. Because several studies reported an association between response and serum Rituximab concentrations, a treatment based on a pharmacokinetic model may be useful for predicting the desired drug concentration.

Amyloidosis↗
PubMed2004

The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL).

Based on the efficacy of thalidomide in multiple myeloma and on its synergy with dexamethasone on myeloma plasma cells, we evaluated the combination of thalidomide (100 mg/d, with 100-mg increments every 2 weeks, up to 400 mg) and dexamethasone (20 mg on days 1-4) every 21 days in 31 patients with primary amyloidosis (AL) whose disease was refractory to or had relapsed after first-line therapy. Eleven (35%) patients tolerated the 400 mg/d thalidomide dose. Overall, 15 (48%) patients achieved hematologic response, with 6 (19%) complete remissions and 8 (26%) organ responses. Median time to response was 3.6 months (range, 2.5-8.0 months). Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction. The combination of thalidomide and dexamethasone is rapidly effective and may represent a valuable second-line treatment for AL.

Adult↗
PubMed2004

Insights into the regulation of immunoglobulin light chain gene rearrangements via analysis of the kappa light chain locus in lambda myeloma.

Accumulating evidence indicates that B cells may undergo sequential rearrangements at the light chain loci, despite already expressing light chain receptors. This phenomenon may occur in the bone marrow and, perhaps, in germinal centers. As immunoglobulin (Ig)kappa light chains usually rearrange before Iglambda light chains, we analysed, by polymerase chain reaction, the Igkappa locus of bone marrow mononuclear cells from 29 patients with Iglambda myeloma to identify earlier recombinations in marrow plasma cells. The results demonstrated that Igkappa alleles were inactivated via the kappa-deleting element, presumably prior to V(kappa)-J(kappa) rearrangement, in many cases. Eighteen alleles (16 myeloma clones, 55%) showed V(kappa)-J(kappa) rearrangements, with increased utilization of 5' distant V(kappa) and 3' distant Jkappa gene segments (Jkappa4, 56%), an indication of multiple sequential rearrangements. In-frame, potentially functional V(kappa)-J(kappa) rearrangements were found in approximately one-third of available rearrangements (as expected by chance), each one in different myeloma clones: three were germline encoded, while one had several nucleotide substitutions, suggesting inactivation after the onset of somatic hypermutation. Three of four potentially functional V(kappa)-J(kappa)rearrangements involved V(kappa)4-1, a segment considered to be associated with autoimmunity. These findings provide insights into the regulation of light chain rearrangements and support the view that B cells may occasionally undergo sequential light chain rearrangements after the onset of somatic hypermutation.

B-Lymphocytes↗
PubMed2004

Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.

BACKGROUND & AIMS: Hereditary systemic amyloidoses are autosomal dominant, late-onset disorders caused by mutations in the genes for a group of plasma proteins including transthyretin, lysozyme, fibrinogen Aalpha chain, gelsolin, apolipoprotein A-I, and apolipoprotein A-II. We investigated both phenotypic and genotypic aspects of apolipoprotein A-I amyloidosis unexpectedly disclosed by liver biopsy in 13 unrelated individuals with asymptomatic, persistent elevation of alkaline phosphatase and gamma-glutamyltransferase levels. METHODS: Immunoelectron microscopy was used for in situ characterization of amyloid deposits on liver biopsy specimens. Mutation analysis was performed by sequencing of the apolipoprotein A-I gene in all patients. Wild-type/variant apolipoprotein A-I ratio in plasma high-density lipoproteins was assessed by a peptide mass fingerprinting approach after purification of total apolipoprotein A-I of 2 patients. RESULTS: Family history was informative in 5 cases. Renal failure developed in 9 cases. Hypogonadism due to testicular involvement was observed. Amyloid fibrils specifically stained with anti-apolipoprotein A-I antibody. A novel (Leu75Pro) heterozygous mutation in the apolipoprotein A-I gene was present in affected individuals but not in controls. Variant apolipoprotein A-I was about 10% of the total protein in high-density lipoproteins. CONCLUSIONS: The high number of individuals with apparently sporadic disease might reflect widespread occurrence of this mutation in the population and a milder phenotype of this variant compared with other apolipoprotein A-I amyloidogenic mutants. These findings suggest that specific staining for amyloid should be performed on liver biopsy of individuals with asymptomatic chronic elevation of alkaline phosphatase and gamma-glutamyltransferase levels.

Aged↗
PubMed2003

Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation.

The most efficient therapeutic approach for immunoglobulin light chain amyloidosis (AL) is autologous stem cell transplantation (ASCT); however, the toxicity of ASCT limits its feasibility to a minority of patients. Patients ineligible for ASCT are usually treated with standard oral melphalan and prednisone, but the response rate to this regimen is unsatisfactory, and time to response is long. High-dose dexamethasone provides a rapid response time in patients with AL. We evaluated the combination of oral melphalan and high-dose dexamethasone (M-Dex) in 46 patients with AL ineligible for ASCT. Thirty-one (67%) achieved a hematologic response and 15 (33%) a complete remission. In 22 (48%) of the responsive patients functional improvement of the organs involved was observed. Five patients (11%) experienced severe adverse events, 3 required hospitalization, and no treatment-related deaths were observed. M-Dex represents a feasible and effective therapeutic option for patients with advanced AL who are ineligible for ASCT.

Adult↗
PubMed2003

Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis.

BACKGROUND: Brain natriuretic peptide (BNP) is a marker of ventricular dysfunction and can be used to assess prognosis in heart failure and after myocardial infarction. Heart involvement is the most important prognostic factor and causes death in almost all patients with light-chain amyloidosis (AL). We investigated the prognostic value of NT-proBNP and its utility in monitoring amyloid heart dysfunction. METHODS AND RESULTS: NT-proBNP was quantified at diagnosis in 152 consecutive patients seen at the coordinating center of the Italian Amyloidosis Study Group (Pavia) from 1999 throughout 2001. Heart involvement was estimated on the basis of clinical signs, electrocardiography, and echocardiography. NT-proBNP concentrations differed in patients with (n=90, 59%) and without (n=62, 41%) heart involvement (median: 507.8 pmol/L versus 22.1 pmol/L, P=10(-7)). The best cutoff for heart involvement was at 152 pmol/L (sensitivity: 93.33%, specificity: 90.16%, accuracy: 92.05%) and distinguished two groups with different survival (P<0.001). The Cox multivariate model including NT-proBNP was better than models including echocardiographic and clinical signs of heart involvement. NT-proBNP appeared to be more sensitive than conventional echocardiographic parameters in detecting clinical improvement or worsening of amyloid cardiomyopathy during follow-up. CONCLUSIONS: NT-proBNP appeared to be the most sensitive index of myocardial dysfunction and the most powerful prognostic determinant in AL amyloidosis. It adds prognostic information for newly diagnosed patients and can be useful in designing therapeutic strategies and monitoring response. NT-proBNP is a sensitive marker of heart toxicity caused by amyloidogenic light chains.

Adult↗
PubMed2002

Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment.

Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with lambda isotype and lambdaVI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal V(lambda) regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the lambdaIII family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the lambdaIII and lambdaVI families, namely 3r (22% of cases, lambdaIII) and 6a (20%, lambdaVI), contributed equally to encode 42% of amyloid V(lambda) regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%, P =.024; 6a, 2.3%, P =.0008, chi2 test); (5) the J(lambda)2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P =.03), and this might be related to preferential J(lambda)2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that V(lambda)-J(lambda) expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments, 3r and 6a, can thus account for the lambda light-chain overrepresentation typical of this disorder.

Adult↗
PubMed2002

Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+ cells with small- and large-scale Miltenyi cell sorting system.

The purging efficacy of the Miltenyi sorting system was evaluated by qualitative and TaqMan quantitative polymerase chain reaction (PCR) in myeloma patients, using immunoglobulin genes. After small-scale selection, qualitative PCR showed that in 6 of 12 leukaphereses myeloma cells were no longer detectable. Envisaging a possible clinical application, the leukaphereses from three patients underwent large-scale selection. Qualitative PCR showed that myeloma cells were still detectable. Quantitative PCR, performed in two patients, showed a tumour depletion of 1 and 2 logs respectively. Although numbers are small, the promising results obtained with small-scale selection were not reproduced in large-scale experiments.

Aged↗