BACKGROUND: We have previously characterized the left ventricular diastolic filling abnormalities in cardiac amyloidosis by Doppler methods. The various filling patterns were shown to be related to the degree of cardiac amyloid infiltration. The purpose of this study was to determine the value of Doppler diastolic filling variables for assessing prognosis in cardiac amyloidosis. METHODS AND RESULTS: We performed pulsed-wave Doppler studies of the left ventricular inflow and obtained clinical follow-up data in 63 consecutive patients with biopsy-proven systemic amyloidosis. All patients had typical echocardiographic features of cardiac involvement. The patients were subdivided into two groups according to deceleration time: Group 1 (33 patients) had a deceleration time of 150 msec or less, indicative of restrictive physiology, and group 2 (30 patients) had a deceleration time of more than 150 msec. Of the 63 patients, 32 (51%) died during a mean follow-up period of 18 +/- 12 months. Of these deaths, 25 (78%) were cardiac deaths, and 19 of the 25 patients (76%) were from group 1. The 1-year probability of survival in group 1 was significantly less than that in group 2 (49% versus 92%, p less than 0.001). Bivariate analysis revealed that the combination of the Doppler variables of shortened deceleration time and increased early diastolic filling velocity to atrial filling velocity ratio were stronger predictors of cardiac death than were the two-dimensional echocardiographic variables of mean left ventricular wall thickness and fractional shortening. CONCLUSIONS: Doppler-derived left ventricular diastolic filling variables are important predictors of survival in cardiac amyloidosis.

Amyloidosis↗

PubMed1991

Speech disorders in systemic amyloidosis.

The purpose of this study was to define more completely the speech disorders that can occur in systemic amyloidosis. Fifty-nine patients with histologically established primary systemic amyloidosis were studied. Of this group, 81% had abnormal voice quality, 43% had abnormal pitch, 7% had abnormal resonation and 15% had abnormal articulation. Twenty-two patients also had abnormal findings at laryngeal examination, consisting of bowing, oedema, thickening, dry irritation and polypoid changes of the vocal folds. Macroglossia was found in 17% of the patients and submandibular swelling in 10%. These results support previous studies which showed that abnormal phonation is a sign of systemic amyloidosis and that abnormal voice is by far the most common abnormal speech sign. The relationship between amyloid deposit and dysphonia was not clear. In 23 patients who had laryngeal examinations, no evidence of actual amyloid deposits was documented.

Adult↗

PubMed1991

Classification of amyloidosis by the detection of clonal excess of plasma cells in the bone marrow.

In 28 cases of amyloidosis, bone marrow was examined to determine whether detection of clonal excess of plasma cells could be used to distinguish immunoglobulin-derived amyloidosis from other forms of amyloidosis. Patients were selected from a group of 315 cases of biopsy-proved amyloidosis in which bone marrow aspiration and biopsy had been done. There was no detectable monoclonal immunoglobulin in the serum or in the urine in 28 patients. Of 13 patients with immunoglobulin-derived amyloidosis, a clonal excess of plasma cells in the bone marrow could be detected in 11 (sensitivity, 85%), even though no immunoglobulin could be found circulating in the serum or urine after immunofixation with two light chain antisera of different sources. The 15 remaining patients had other forms of amyloidosis; 14 had polyclonal populations of plasma cells in the bone marrow (specificity, 93%). The positive predictive value of clonal excess was 92% and its negative predictive value was 88%. We conclude that, in the subset of patients with amyloidosis who do not have a circulating M component in the serum or urine detection of a clonal excess of plasma cells is useful in characterizing the type of amyloidosis. Correct classification is important for appropriate assessment of prognosis and therapy for the group of patients.

Adult↗

PubMed1991

Strategies for combining interferon with chemotherapy for the treatment of multiple myeloma.

Interferon has been evaluated in many settings for the treatment of multiple myeloma. As a single agent in refractory disease, interferon in partially purified preparations and, more recently, recombinant alpha-interferon (rIFN) has demonstrated response rates of 10% to 20%. Because of its demonstrated activity as a single agent, various combinations of rIFN with chemotherapy have been evaluated. The Italian Myeloma Study Group has found that maintenance therapy with rIFN alpha 2b prolongs the time to relapse following a year of standard chemotherapy. The Cancer and Acute Leukemia Group B has evaluated a regimen that combines rIFN alpha 2b with simultaneous melphalan and prednisone. In a third approach, the Eastern Cooperative Oncology Group has developed a regimen consisting of alternating cycles of VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) chemotherapy with rIFN alpha 2b. This regimen yields an 80% objective response rate, including 30% complete responses defined by disappearance of M-protein from serum and urine and complete morphologic normalization of the bone marrow. On preliminary analysis, the response duration and median survival were both approximately 1 year longer than generally observed in patients with multiple myeloma on standard regimens. Hematologic toxicity, although more severe than that observed previously with VBMCP alone, was not associated with increased infections or bleeding. To substantiate the observation of apparent increased activity of VBMCP + rIFN alpha 2b, the Eastern Cooperative Oncology Group is currently conducting a randomized comparison of this regimen with treatment using VBMCP alone.

Antineoplastic Agents↗

PubMed1991

Secondary systemic amyloidosis: response and survival in 64 patients.

From 1956 through 1989, 38 men and 26 women were seen at the Mayo Clinic with biopsy-proven AA. The underlying disorder was rheumatic disease in 42, infectious disease in 11, inflammatory bowel disease in 6, and other causes in 5. All patients were symptomatic at the time of diagnosis. Fifty-eight of the 64 patients had proteinuria or renal insufficiency. Fourteen also had significant symptoms of gastrointestinal amyloid, and 6 had amyloid goiter. None of the patients had symptomatic cardiac involvement, and only 3 had palpable hepatomegaly. Renal, gastric, rectal, fat, and marrow biopsies were positive for amyloid in 100%, 94%, 82%, 58%, and 46% of tested patients, respectively. The median survival of the entire group was 24.5 months. Thirty-five of the 47 deceased patients died as a direct result of their amyloidosis, primarily from complications of renal failure. Nine were successfully treated and had regression of the disease. Two with bronchiectasis responded to long-term cyclic antibiotic therapy, as did 1 patient with osteomyelitis. One patient with inflammatory bowel disease responded to surgical resection, and 1 with familial Mediterranean fever responded to colchicine. Four patients with rheumatic disease were treated with cyclophosphamide (in 2) and methotrexate (in 2), with complete resolution of their renal disease. All 9 successfully treated patients are alive, with a median follow-up of 58 months. Statistical analysis revealed that creatinine values greater than or equal to 2.0 mg/dl (P less than 0.003) and a serum albumin value less than 2.5 g/dl (P less than 0.02) were associated with a poorer survival. The single strongest variable associated with poor survival was a serum creatinine level greater than 2 mg/dl at presentation, with a median survival of 11.2 months compared to patients with a creatinine level less than 2.0 mg/dl, with a median survival of 56.9 months.

Adolescent↗

PubMed1990

Newer approaches to the therapy of multiple myeloma.

Explore the source record for details and available documents.

Bone Marrow Transplantation↗

PubMed1990

Phase II trial of alpha-tocopherol (vitamin E) in the treatment of primary systemic amyloidosis.

Primary systemic amyloidosis (AL) is a rare disorder characterized by deposition of a monoclonal immunoglobulin light chain or fragment thereof, resulting in dysfunction of the heart, kidney, liver, or nerves. Despite the use of melphalan, prednisone, colchicine, and dimethyl sulfoxide (DMSO), no improvement in median survival has been reported in prospective randomized studies. We undertook a study of alpha-tocopherol acetate (vitamin E) in the treatment of 16 patients with AL because of its reported benefits in animal models of senile and secondary amyloidosis as well as reported benefit in the treatment of secondary amyloidosis in humans. None of the patients showed any objective regression of their disease. The median survival of the entire group was 19.4 months. This survival is not superior to that reported with other agents used in this disease. We conclude that alpha-tocopherol is not a valuable agent in the treatment of AL.

Adult↗

PubMed1990

Beta 2-microglobulin predicts survival in primary systemic amyloidosis.

PURPOSE: The study assessed whether beta 2-microglobulin levels predict survival or response in patients with primary systemic amyloidosis without associated multiple myeloma. PATIENTS AND METHODS: The study group consisted of 131 untreated patients with biopsy-proven primary systemic amyloidosis diagnosed and evaluated at the Mayo Clinic. No patient had multiple myeloma. The minimum follow-up of surviving patients is 8 years. No patient was lost to follow-up. RESULTS: The median survival of patients with an increased beta 2-microglobulin level was 10.8 months, compared with patients with a normal beta 2-microglobulin level (less than or equal to 2.7 micrograms/mL, 0.23 mumol/L) of 32.9 months (p less than 0.001). In a multivariate proportional-hazards model, the best model included congestive heart failure (p less than 0.0001) and increased beta 2-microglobulin levels (p less than 0.05). After adjustment for the presence of congestive heart failure, beta 2-microglobulin level remained significant. When the analysis was restricted to those patients with normal renal function, the median survival of those with an elevated beta 2-microglobulin level was 9.1 months versus 39.4 months for those with a normal level (p less than 0.001). The serum level of beta 2-microglobulin was increased in patients with nephrotic-range proteinuria with or without renal insufficiency (p = 0.05). CONCLUSION: The serum beta 2-microglobulin level should be measured routinely in all patients with primary systemic amyloidosis because it provides a useful objective factor to identify subsets of patients with this disease who have unfavorable outcomes.

Adult↗

PubMed1990

The second riboflavin-binding myeloma IgG lambdaDOT. I. Biochemical and functional characterization.

A human monoclonal immunoglobulin, IgGDOT, with flavin-binding capacity has been obtained from an elderly woman with multiple myeloma who developed yellow skin and yellow hair. The case presented a remarkable similarity with that previously reported by Farhangi and Osserman [N. Engl. J. Med. 294, 177-183 (1976)]. Purified IgGDOT was bright yellow and the ligand was identified as riboflavin and its oxidation products by thin layer chromatography, proton nuclear magnetic resonance and mass spectroscopy. Competitive binding studies with different haptens demonstrated highest affinity for riboflavin, followed by flavin mononucleotide and flavin adenine dinucleotide; no significant binding was detected for several other non-flavin compounds tested. The hapten was associated with the protein in vivo, as well as with the purified antibody. Removal of the already bound riboflavin from the combining site was associated with irreversible denaturation of the monoclonal protein. By the fluorescence quenching technique it was determined that there were 0.68 available combining sites for riboflavin molecule in IgGDOT with a binding constant of 8.5 x 10(8)/M, while FabDOT presented 0.27 available combining sites with a binding constant of 5.1 x 10(8)/M. The fact that 1.2 and 0.81 mol riboflavin/mol protein were already bound to IgGDOT and FabDOT, respectively, is consistent with the usual hapten/antibody stoichiometry. The heavy chain subclass of IgGDOT was identified as gamma 2, as in the previously reported case of riboflavin-binding protein IgGGAR. However, the lambda chain subclass was different and no idiotype cross-reactivity was found.

Aged↗