Showing papers by "Martha Skinner published in 2003"

Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis.

Abstract: Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.

Bone marrow core biopsy specimens in AL (primary) amyloidosis. A morphologic and immunohistochemical study of 100 cases.

Abstract: We retrospectively reviewed 100 bone marrow core biopsy specimens from patients with AL (primary) amyloidosis. The morphologic and immunohistochemical features were assessed by standard histochemical stains (HE κ, 18) of cases. Amyloid deposits were observed in 60% of the bone marrow core biopsy specimens and, when present, were detected most often in blood vessel walls only (39/60). However, if present, interstitial amyloid deposition was significantly more associated with patients with a monoclonal κ light chain gammopathy (P = .04). Through the careful analysis of standard histochemical and immunohistochemical stains, bone marrow core biopsy provides essential diagnostic information in cases of AL amyloidosis. AL (primary) amyloidosis is the most common form of systemic amyloidosis seen in the United States and is due to an underlying plasma cell dyscrasia that produces an amyloidogenic light chain, which deposits as amyloid fibrils within tissues. 1 The prognosis of AL amyloidosis is poor, with a median survival of 1 to 2 years but, recently, improved survival has been seen with more aggressive therapy using high-dose melphalan and autologous stem cell transplantation. 2 Once the initial histologic diagnosis of amyloid deposition is made, subsequent typing for AL amyloidosis is dependent on the identification of monoclonal light chains by serum and/or urine immunofixation electrophoresis (IFE). Bone marrow core biopsy is performed to identify the underlying plasma cell dyscrasia present and to exclude plasma cell myeloma. Morphologic features of the bone marrow core biopsy specimen in patients with AL amyloidosis are subtle, and often the diagnosis may be missed when examining routine histochemical stains. The identification of a monoclonal population of plasma cells by using immunohistochemical techniques on bone marrow core biopsy specimens sometimes is difficult because of the low number of plasma cells present. The aim of this study was to assess the morphologic and immunohistochemical bone marrow features in a large group of cases of AL amyloidosis. In addition, we describe how bone marrow core biopsy supplements other diagnostic tests that are used in the initial evaluation of patients for AL amyloidosis.

Bone Marrow Core Biopsy Specimens in AL (Primary) Amyloidosis

Abstract: We retrospectively reviewed 100 bone marrow core biopsy specimens from patients with AL (primary) amyloidosis. The morphologic and immunohisto-chemical features were assessed by standard histochemical stains (HEκ, 18) of cases. Amyloid deposits were observed in 60% of the bone marrow core biopsy specimens and, when present, were detected most often in blood vessel walls only (39/60). However, if present, interstitial amyloid deposition was significantly more associated with patients with a monoclonal κ light chain gammopathy ( P = .04). Through the careful analysis of standard histochemical and immunohistochemical stains, bone marrow core biopsy provides essential diagnostic information in cases of AL amyloidosis.

Identification of S-sulfonation and S-thiolation of a novel transthyretin Phe33Cys variant from a patient diagnosed with familial transthyretin amyloidosis

Abstract: Familial transthyretin amyloidosis (ATTR) is an autosomal dominant disorder associated with a variant form of the plasma carrier protein transthyretin (TTR). Amyloid fibrils consisting of variant TTR, wild-type TTR, and TTR fragments deposit in tissues and organs. The diagnosis of ATTR relies on the identification of pathologic TTR variants in plasma of symptomatic individuals who have biopsy proven amyloid disease. Previously, we have developed a mass spectrometry-based approach, in combination with direct DNA sequence analysis, to fully identify TTR variants. Our methodology uses immunoprecipitation to isolate TTR from serum, and electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry (MS) peptide mapping to identify TTR variants and posttranslational modifications. Unambiguous identification of the amino acid substitution is performed using tandem MS (MS/MS) analysis and confirmed by direct DNA sequence analysis. The MS and MS/MS analyses also yield information about posttranslational modifications. Using this approach, we have recently identified a novel pathologic TTR variant. This variant has an amino acid substitution (Phe → Cys) at position 33. In addition, like the Cys10 present in the wild type and in this variant, the Cys33 residue was both S-sulfonated and S-thiolated (conjugated to cysteine, cysteinylglycine, and glutathione). These adducts may play a role in the TTR fibrillogenesis.

Spontaneous rupture of the spleen in AL amyloidosis

Abstract: The frequency of splenic involvement in AL amyloidosis is not precisely known. However, splenomegaly has been reported in 4-13% of patients. We report four cases of spontaneous splenic rupture in patients with AL amyloidosis. Splenic rupture was the initial manifestation of the disease in one of these patients. The other three experienced splenic rupture during or after high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT): one during stem cell mobilization with G-CSF prior to HDM/SCT and two after hematopoietic recovery following treatment. Two of the four patients had Factor X deficiency, the most common coagulation abnormality associated with AL amyloidosis. All four patients underwent splenectomy without significant postoperative complications. Splenic rupture in AL amyloidosis as a complication of aggressive treatment with HDM/SCT has not been reported previously.

Endothelial dysfunction precedes C-fiber abnormalities in primary (AL) amyloidosis.

Abstract: Primary (AL; immunoglobulin light-chain associated) amyloidosis is characterized by the deposition of pathological proteins in the extracellular matrix of tissues and organs. Autonomic and sensory peripheral neuropathy is a common feature of this disorder. The pathogenesis of the neuropathy is poorly defined. The aims of this study were to investigate vascular and neural function in the cutaneous microcirculation of AL amyloidosis patients. Seven patients with AL amyloidosis and controls were studied. Acetylcholine and sodium nitroprusside were iontophoresed into the forearm skin. Endothelial, smooth muscle, and C-fiber-mediated cutaneous blood flow (CuBF) were recorded by laser Doppler flowmetry. Endothelial vasodilation in the forearm skin was attenuated in AL amyloidosis patients (p = 0.007). Maximum endothelium-mediated CuBF in the patient group was reduced (p = 0.047). No group differences could be detected in the C-fiber response or smooth muscle vasodilation (p value not significant). Maximum C-fiber and endothelium-independent CuBF did not differ between the two groups (p value not significant). Early in the disease, AL amyloidosis patients present with impaired endothelial function. At this stage, C-fiber and smooth muscle function are still preserved. These data suggest that endothelial abnormalities precede and may contribute to the pathogenesis of the neuropathy associated with AL amyloidosis.