Bortezomib-dexamethasone versus high-dose melphalan for Japanese patients with systemic light-chain (AL) amyloidosis: a retrospective single-center study.

Bortezomib-dexamethasone (BD) and high-dose melphalan (HDM) are effective for systemic light-chain (AL) amyloidosis, but have not been compared in detail. We retrospectively investigated patients treated with BD or HDM at our center between September 2001 and June 2016. Among 234 patients, 20 were treated with BD and 30 received HDM. With the exception of age, transplant eligibility, and previous history of other chemotherapy, there were no significant differences in most background parameters between the two groups. Median age was higher (63.2 vs. 55.8, P = 0.001), number of transplant-eligible patients was lower (60.0 vs. 96.7%, P = 0.002), and number of previously treated patients was higher (35.0 vs. 0.0%, P < 0.001) in the BD group. The BD group showed trends toward lower treatment-related mortality (5.0 vs. 10.0%, P = 0.641), greater hematological response (partial response or better) (90.0 vs. 73.3%, P = 0.279), higher complete response (60 vs. 50%, P = 0.487), and similar survival with the HDM group (neither reached, P = 0.705). In conclusion, BD was as effective and safe as HDM. Notably, BD achieved this outcome among patients with poorer clinical backgrounds compared with HDM.

Patient with adult-onset type II citrullinemia beginning 2 years after operation for duodenal malignant somatostatinoma: Indication for liver transplantation.

We report a 51-year-old female patient with adult-onset type II citrullinemia (CTLN2) who had a history of pancreatoduodenectomy for duodenal somatostatinoma with metastases to regional lymph nodes at age 49 years, paying special attention to indications for liver transplantation. At age 50 years, she developed hepatic encephalopathy with elevation of plasma ammonia and citrulline levels. A diagnosis of CTLN2 was made by DNA analysis of the SLC25A13 gene and treatment with conservative therapies was begun, including a low-carbohydrate diet and supplementation with arginine and sodium pyruvate. However, despite these treatments, frequent attacks of encephalopathy occurred with markedly elevated plasma ammonia levels. While we were apprehensive regarding the risk of recurrence of somatostatinoma due to immunosuppressive therapy after liver transplantation, the patient was in a critical condition with CTLN2 and it was decided to perform living-donor liver transplantation using a graft obtained from her son. Her postoperative clinical course was uneventful and she has had an active life without recurrence of somatostatinoma for 2 years. This is the first case of CTLN2 with somatostatinoma. As the condition of CTLN2 patients with rapidly progressive courses is often intractable by conservative therapies alone, liver transplantation should be considered even after surgery for malignant tumors in cases with neither metastasis nor recurrence.

Surgical removal of amyloid-laden lymph nodes: a possible therapeutic approach in a primary systemic AL amyloidosis patient with focal lymphadenopathy.

We report a patient with primary systemic AL amyloidosis who suffered from remarkable bilateral cervical lymphadenopathy. Intensive chemotherapies, including two cycles of high-dose melphalan with autologous peripheral blood stem cell transplantation, were insufficiently effective for both the lymphadenopathy and amyloidogenic IgGλ-type M-protein in serum, but the patient showed complete haematological remission after extensive surgical removal of enlarged lymph nodes that had massive depositions of λ-type immunoglobulin light chain-derived amyloid. Lymphadenectomy may be a possible therapeutic approach with regard to both cosmetic and haematological aspects in primary systemic AL amyloidosis patients with focal lymphadenopathy.

Marked shrinkage of amyloid lymphadenopathy after an intensive chemotherapy in a patient with IgM-associated AL amyloidosis.

A male patient with primary AL amyloidosis who had been suffering from systemic lymphadenopathy with IgMkappa-type M-proteinemia received two courses of VAD and high-dose melphalan with in vivo elimination of CD20(+) cells using rituximab followed by autologous peripheral blood stem cell transplantation. Four years after complete hematological remission he showed marked reduction in size of the amyloid-laden lymph nodes. Deposits of AL amyloid may regress from the tissue if the chemotherapy succeeds in persistent inhibition of the production of an amyloidogenic immunoglobulin light chain.

Marked shrinkage of amyloid lymphadenopathy after an intensive chemotherapy in a patient with IgM-associated AL amyloidosis.

A male patient with primary AL amyloidosis who had been suffering from systemic lymphadenopathy with IgMkappa-type M-proteinemia received two courses of VAD and high-dose melphalan with in vivo elimination of CD20(+) cells using rituximab followed by autologous peripheral blood stem cell transplantation. Four years after complete hematological remission he showed marked reduction in size of the amyloid-laden lymph nodes. Deposits of AL amyloid may regress from the tissue if the chemotherapy succeeds in persistent inhibition of the production of amyloidogenic immunoglobulin light chains.

Long-term follow-up of plasma cells in bone marrow and serum free light chains in primary systemic AL amyloidosis.

OBJECTIVE: Primary systemic AL amyloidosis arises from immunoglobulin light chains produced by plasma cell dyscrasia. To prospectively investigate the production of M-protein and plasma cells in bone marrow before and after chemotherapy, we performed flow cytometry and analysis of serum free light chains (FLCs). PATIENTS AND METHODS: Fifty-nine patients with primary systemic AL amyloidosis (mean age, 59.9+/-8.8 years) were enrolled in this study, and of these 31 were serially studied before and after chemotherapy. Complete hematological remission was defined as normalization of the FLC kappa/lambda ratio. RESULTS: MPC-1(-)CD45(-) (p<0.05) and MPC-1(+)CD45(-)CD49e(-) (p<0.005) were significantly higher, and MPC-1(-)-CD45(+) (p<0.05), MPC-1(+)CD45(+)CD49e(-) (p<0.0001) and MPC-1(+)CD45(+)CD49e(+) (p<0.0005) were significantly lower in the patients with AL amyloidosis than in controls. There was a significantly positive correlation between the serum predominant FLC/serum creatinine ratio and MPC-1(+)CD45(-)CD49e(-) (p<0.05). After chemotherapies, such as high-dose melphalan with autologous stem cell support, 20 of 31 patients with AL amyloidosis achieved complete hematological remission. There were no significant differences in any subtype of plasma cells before treatment between the remission and non-remission groups, but in the former group MPC-1(+)CD45(-)CD49e(-) and MPC-1(-)CD45(+) were significantly decreased and increased after chemotherapy compared with before, respectively. CONCLUSION: Abnormal plasma cells in the bone marrow, particularly the MPC-1(+)CD45(-)CD49e(-) subset, may be important as a follow-up marker before and after chemotherapy in primary systemic AL amyloidosis. These cells maintain low levels as long as no relapse occurs.

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.

Systemic AL amyloidosis mimicking rheumatoid arthritis.

We report a patient with myeloma-associated systemic AL amyloidosis who showed chronic polyarthralgia as the main symptom. The clinical picture was similar to that of rheumatoid arthritis with regard to symmetrical swelling with tenderness in multiple joints, but inflammatory reactions were almost normal and autoantibodies were negative. He was diagnosed as having systemic AL amyloidosis based on deposition of kappa-light chain-immunoreactive amyloid in biopsied tissue and Bence Jones protein in serum and urine. Magnetic resonance imaging and bone scintigraphy suggested this disease as the cause of the polyarthralgia. Systemic AL amyloidosis may be important in the differential diagnosis of chronic polyarthralgia.

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.

Successful treatment with infliximab and low-dose methotrexate in a Japanese patient with familial Mediterranean fever.

We report a Japanese patient with familial Mediterranean fever (FMF) who was successfully treated with the anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab, and low-dose methotrexate. This patient was diagnosed as having FMF based on periodic fever with polyarthralgia typical of this disease and heterozygous mutations in the MEFV gene. Conventional treatment, such as colchicine and reserpine, failed to sufficiently control the FMF attacks. After starting infliximab (3 mg/kg) and low-dose methotrexate (6 mg/week), the frequency of the FMF attacks dramatically decreased and the clinical effect has remained unchanged for longer than 1 year. Combination therapy with infliximab and low-dose methotrexate may be a potent therapeutic option for FMF patients, particularly when conventional treatment is ineffective or cannot be employed because of adverse events.

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.

Severe cranial nerve involvement in a patient with monoclonal anti-MAG/SGPG IgM antibody and localized hard palate amyloidosis.

We report a patient with severe cranial polyneuropathy as well as sensory limb neuropathy. Biclonal serum IgM-kappa/IgM-lambda gammopathy was found and serum anti-myelin-associated glycoprotein (MAG)/sulfoglucuronyl paragloboside (SGPG) IgM antibody was also detected. Immunofluorescence analysis of a sural nerve biopsy specimen revealed binding of IgM and lambda-light chain on myelin sheaths. No amyloid deposition was detected in biopsied tissues except for the hard palate, suggesting that the amyloidosis was of the localized type and had no relation to the pathogenesis of cranial neuropathy. Our observations indicate that the anti-MAG/SGPG IgM antibody may be responsible for this patient's cranial polyneuropathy, which is a rare manifestation in anti-MAG/SGPG-associated neuropathy.