Therapeutic outcome of cyclic VAD (vincristine, doxorubicin and dexamethasone) therapy in primary systemic AL amyloidosis patients.

OBJECTIVE: Intensive chemotherapy targeting plasma cell dyscrasia has been recently employed for the treatment of primary systemic AL amyloidosis. We prospectively studied the clinical usefulness of cyclic VAD (vincristine, doxorubicin and dexamethasone) in patients with primary systemic AL amyloidosis who were ineligible for high-dose melphalan with autologous stem cell support. PATIENTS AND METHODS: Eight patients (mean age, 60.4+/-8.8 years) were treated with cyclic VAD until the disappearance of M-protein from both serum and urine. Of these, seven showed nephrotic syndrome before the start of VAD irrespective of a decrease in creatinine clearance. Serial follow-up studies after VAD evaluated hematological status and organ function. RESULTS: Four patients (50%) showed a marked decrease in abnormal plasma cells in the bone marrow and normalized kappa/lambda ratios of serum free light chain in conjunction with disappearance of M-protein after 1 to 3 courses of VAD. There were no serious adverse events, and nephrotic syndrome gradually improved with no hematological relapse in the follow-up period of 3 to 5 years. The remaining 4 patients showed worsening of congestive heart failure and/or systemic edema ascribable to dexamethasone, resulting in cessation of cyclic VAD before disappearance of M-protein. All of these patients died of multiple organ failure or required permanent hemodialysis within 1 year after the start of cyclic VAD. CONCLUSION: Cyclic VAD is a potent therapeutic option in primary systemic AL amyloidosis, but in patients with renal or cardiac dysfunction careful management for adverse events, especially body fluid retention, is necessary.

Nephrotic syndrome due to primary systemic AL amyloidosis, successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone.

We report 3 patients with nephrotic syndrome ascribed to primary systemic AL amyloidosis that were successfully treated with VAD (vincristine, doxorubicin and dexamethasone) alone. M-protein in serum disappeared soon after VAD, and nephrotic syndrome gradually improved in parallel with a decrease in daily protein excretion in urine. Long-term follow-up of these patients showed neither relapse of nephrotic syndrome nor reappearance of M-protein. High-dose melphalan followed by autologous stem cell support is a standard therapy for primary systemic AL amyloidosis, but in high-risk cases for this treatment, such as elderly patients and those with multiple organ involvement, VAD might be a therapeutic option.

Histopathological regression of systemic AA amyloidosis after surgical treatment of a localized Castleman's disease.

Previously, we reported a case of localized plasma cell type Castleman's disease with severe hepatomegaly and reactive systemic AA amyloidosis. The amyloid deposits were demonstrated in both the hepatic tissue and in the gastric mucosa. Surgical resection of an isolated extra-hepatic tumor was performed. The laboratory findings, including SAA and IL-6, remained within normal limits and the patient's hepatomegaly subsequently showed regression. Nine years after the operation, no amyloid deposition was seen in the gastric mucosa and the patient's liver was of normal size. Our findings with long-term follow up in this case indicated that the cessation of SAA production was the probable cause of histopathological regression of AA amyloid deposits in this patient.

AH amyloidosis associated with lymphoplasmacytic lymphoma secreting a monoclonal gamma heavy chain carrying an unusual truncated D segment.

To date, the presence of amyloidosis associated with immunoglobulin heavy chain (AH amyloidosis) was reported in only 7 cases. Although AH amyloidosis is caused mainly by plasma cell dyscrasia, as in AL amyloidosis, we report a 61-year-old patient who presented with nephrotic syndrome caused by AH amyloidosis associated with lymphoplasmacytic lymphoma. Biochemical and molecular analyses of the deposited amyloid fibrils and heavy-chain genes of lymphocytes showed that proliferative lymphoma cells produced a gamma heavy chain, not a mu heavy chain, which carried an unusual truncated diversity (D) segment of the variable region. Our results indicate that production of the abnormal heavy chain caused by the partially deleted D segment gene is responsible for gamma heavy-chain-related amyloid fibril formation in this patient.

Correlation between serum levels of free light chain and phenotype of plasma cells in bone marrow in primary AL amyloidosis.

To investigate whether there is a correlation between subtypes of plasma cells in the bone marrow and the production of M-protein, flow cytometry and serum free light chain (FLC) analyses were carried out in 17 patients with primary systemic AL amyloidosis (mean age, 59.9+/-8.8 years) and controls with M-protein (MGUS controls, n=6) and without it (negative controls, n=9). The patients showed a significantly higher value in the serum predominant FLC:serum creatinine ratio (43.8+/-63.2) and CD38++ CD19- CD56+ subpopulation (monoclonal plasma cells) (2.57+/-5.35%) than either the negative (p<0.0005 and p<0.001, respectively) or MGUS controls (p<0.05). With respect to maturation of plasma cells in the bone marrow, the intermediate (MPC-1+ CD45- CD49e-) and mature (MPC-1+ CD45+ CD49e-) subtypes were significantly higher (49.2+/-23.2%, p<0.005) and lower (27.6+/-21.3%, p<0.005) in the patients than in the negative controls, respectively. The serum predominant FLC:serum creatinine ratio was elevated in parallel with an increase in CD38++ CD19- CD56+ and MPC-1+ CD45- CD49e- cells and a decrease in mature subtypes (MPC-1+ CD45+ CD49e- and MPC-1+ CD45+ CD49e+ cells), There was a significantly positive correlation between the serum predominant FLC:serum creatinine ratio and either CD38++ CD19- CD56+ (r=0.510, p<0.05) or MPC-1+ CD45- CD49e- cells (r=0.481, p<0.05). In primary AL amyloidosis M-protein is probably produced by increased monoclonal plasma cells in the bone marrow, particularly by the intermediate subpopulation with a phenotype of MPC-1+ CD45- CD49e-.

Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide.

This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by 99mTc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on 99mTc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis.

Serum levels of free light chain before and after chemotherapy in primary systemic AL amyloidosis.

OBJECTIVE: Immunoglobulin-related free light chains (FLCs) in serum have recently become quantitatively detectable using the nephelometric assay in plasma cell disorders, including multiple myeloma and AL amyloidosis. To investigate whether FLCs are useful as a diagnostic and therapeutic marker in Japanese patients with primary systemic AL amyloidosis, we determined these values in serum before and after chemotherapy. PATIENTS AND METHODS: The serum FLC analysis was carried out in 25 patients with primary systemic AL amyloidosis (mean age, 60.1+/-8.4 years). All of the patients were shown to have either ALkappa- or ALlambda-immunoreactive amyloid deposits on biopsied tissues. Thirteen patients were treated with VAD (vincristine, doxorubicin and dexamethasone) alone (n=6) or VAD and subsequent high-dose melphalan followed by autologous stem cell support (n=7), and serum FLCs were serially determined before and after the chemotherapy. RESULTS: Before chemotherapy the amyloidogenic FLC was elevated in serum with or without abnormal e/e ratios in 24 patients, including 5 with undetectable M-protein in both serum and urine on immunofixation. After chemotherapy the amyloidogenic FLC in serum was significantly decreased irrespective of high-dose melphalan (p<0.05), and all the patients with normalized kappa/lambda ratios showed a good prognosis. CONCLUSIONS: With respect to sensitivity and quantification serum FLCs will be a key marker for diagnosis and therapeutic effects in primary systemic AL amyloidosis. The prognosis of patients with this disease may be improved if the kappa/lambda ratio in serum can be normalized by intensive chemotherapy.

Sarcoidosis with high serum levels of vascular endothelial growth factor (VEGF), showing RS3PE-like symptoms in extremities.

We report a patient with sarcoidosis who showed edema in the distal portion of all extremities, particularly the legs, as seen in remitting seronegative symmetrical synovitis with pitting edema (RS3PE). Magnetic resonance imaging demonstrated diffuse abnormal intensity in subcutaneous tissues of both legs, and skin biopsy led to a diagnosis of sarcoidosis. Vascular endothelial growth factor (VEGF) showed a high serum level, which decreased soon after starting oral prednisolone, in parallel with an improvement in the limb edema. In this patient VEGF as well as infiltration by sarcoid granuloma in the skin might have played an important role in the pathogenesis of RS3PE-like symptoms in the extremities. When painful pitting edema is seen predominantly in the distal portion of all extremities, sarcoidosis as well as RS3PE should be considered as a possible diagnosis.

A patient with severe renal amyloidosis associated with an immunoglobulin gamma-heavy chain fragment.

The authors report a patient with progressive renal dysfunction caused by severe renal amyloidosis associated with a gamma-heavy chain variable region (V(H)) fragment. The patient was a 71-year-old woman who had renal insufficiency without nephrotic syndrome. Laboratory data showed a monoclonal IgG lambda component in her serum and urine. Renal biopsy results showed massive amyloid deposition in the mesangial region, but the glomerular basement membranes and epithelial cells were preserved. Because immunohistochemical studies using antibodies against a number of known amyloid fibril proteins failed to detect the amyloid protein, the amyloid protein extracted from a small piece of the biopsied renal tissue was subjected to biochemical analysis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the extracted amyloid protein showed a prominent band at 11-kDa, and this protein was identified by amino acid sequence analysis as a gamma-heavy chain variable region fragment (V(H)3 subgroup) without the first N-terminal residue. Our results indicate that the patient's renal amyloidosis was associated with a gamma-heavy chain variable region fragment. Microextraction and biochemical characterization of amyloid fibrils was of great use for reaching a definitive diagnosis.

Bilateral localized amyloidosis of the ureters: clinicopathology and therapeutic approaches in two cases.

Localized amyloidosis in the ureter is a rare condition, in which immunoglobulin light chain is locally synthesized, causing thickening of ureteric walls by deposits of immunoglobulin-related amyloid. Since the clinical features of ureteral amyloidosis with ureteric stricture and/or hydroureteronephrosis closely resemble those of malignancy involving the ureters, nephroureterctomy is usually performed for this disease. We describe two aged patients with localized amyloidosis on the bilateral ureters. In both cases, left hydronephrosis with left ureteral stricture was found. They were treated with total nephroureterctomy and Alambda amyloid deposition was confirmed in the resected ureters. Several months later right ureteral stenosis was found. One patient was treated with percutaneous nephrostomy to preserve his renal function and the other with corticosteroids. This appeared to result in significant regression of the stenotic lesion. In both cases, all examinations for systemic involvement of organs were negative. Corticosteroids may be of use in treating immunoglobulin-derived localized amyloidosis in the ureters.

Histomorphometric features of bone in patients with primary and secondary hypoparathyroidism.

BACKGROUND: Idiopathic adynamic bone disease (ABD) in dialysis patients is characterized by low serum parathyroid hormone (PTH) concentration. Whether ABD itself causes serious disease is controversial. Fuller understanding of both primary hypoparathyroidism and secondary hypoparathyroidism resulting in a long-standing low-PTH state may shed light on properties of ABD. METHODS: We performed histomorphometric analysis in bone specimens from biopsy in two female patients with primary hypoparathyroidism and in an autopsy specimen of bone from a male patient with secondary hypoparathyroidism related to long-term hemodialysis; respective ages, 45, 58, and 65 years; dialysis duration, 6 years, 2 months, and 30 years; lumbar bone mineral density, 2.88, 2.43, and 4.1 SD above the normal mean; and serum intact PTH, <5, <20, and <84 pg/mL (mean, 30.4). Tetracycline labeling was performed in the first two cases. RESULTS: Histomorphometric analysis in the first two cases indicated a diagnosis of ABD, since no tetracycline labeling could be seen along most of trabecular bone surfaces, total osteoid volume was decreased, and fibrous tissue was minimal. Bone volume was preserved, and the dense bone-trabecular connectivity was noted, with normal lamellar structure. A small number of hump-like structures protruded from the quiescent surface of trabecular bone, a pattern which has been called "minimodeling." Tetracycline label was observed in only a small area within trabecular bone in patient 1, and at a region of trabecular bone surface showing minimodeling in patient 2. The third case was also diagnosed as ABD; cancellous lamellar structure and bone volume were normal, although trabecular connectivity was poor and island bone was relatively prominent. Minimodeling was evident. Minimodeling bone volume/total bone volume in these three cases was 9.0%, 13.1%, and 6.8%, respectively; number of minimodeling sites/total bone volume (N/mm2) was 4.9, 8.6, and 9.0, respectively. CONCLUSION: Bone formation mechanism by minimodeling might contribute to preserving bone volume in dialysis patients with hypoparathyroidism, even in the absence of remodeling stimulated by PTH.