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Light chain amyloidosis (AL) is one of the most common forms of systemic amyloidosis and is caused by the deposition of insoluble fibrils derived from misfolded and aggregated immunoglobulin light chains (LC). To uncover the causes leading to this aggregation, we compared AL LC sequences with those of patients with the related disease multiple myeloma (MM), which do not aggregate in insoluble fibrils in vivo. IGLV2‐14 is one of the most common AL‐associated IGLV subfamilies. Here, we analysed IGLV2‐14 LC sequences of 13 AL and eight MM patients in detail. We found that AL‐associated LCs presented a lower median mutation count (7.0 vs. 11.5 in MM; P = 0.045), as well as an overall composition of less charged amino acids than MM LCs. However, we did not find a mutation that was present in ≥ 50% of the AL and not in the MM sequences. Furthermore, we did not find a significant difference in the isoelectric point (pI) in general, suggesting similar stability of the LCs in AL and MM. However, the subgroup of patients without a detectable heavy chain stood out. Surprisingly, they are characterized by an increase in mutation count (median 7.0 vs. 5.5) and pI (median 7.82 vs. 6.44, P = 0.043). In conclusion, our data suggest that the amount of mutations and the introduction of charges play a crucial role in AL fibril formation, as well as the absence or presence of a potential heavy chain binding partner. [ABSTRACT FROM AUTHOR]

Aims: Wildtype transthyretin amyloid cardiomyopathy is an under‐recognized cause of heart failure in elderly patients. Transcatheter tricuspid valve repair is a newly emerging therapeutic option for severe tricuspid regurgitation (TR). We present first insights into safety and possible benefits of this procedure in patients with cardiac amyloidosis. Methods and results: Eight patients with cardiac non‐hereditary (wildtype) transthyretin (ATTRwt) amyloidosis and severe to torrential TR, undergoing successful transcatheter tricuspid valve repair, were included in the analysis and compared to a control group of 21 patients without cardiac amyloidosis. All patients presented with an advanced stage of amyloid cardiomyopathy. Primary endpoint was reduction in TR at 3 months follow‐up. Secondary endpoints were feasibility, safety, hospitalization or death, clinical improvement, cardiac biomarkers, and structural and functional right heart parameter obtained by echocardiography. Transcatheter tricuspid valve repair resulted in a significant reduction of TR (IV to II, P = 0.008) in all eight patients with cardiac amyloidosis (100%). Device success (amyloidosis 75% vs. control group 86%, P = 0.597) and overall probability of hospitalization or death (amyloidosis 13% vs. control group 25%, P = 0.646) were similar compared with those in the control group at 3 months follow‐up. Transcatheter tricuspid valve repair led to an improvement of New York Heart Association functional class (P = 0.031) and 6 min walking distance (from 313 ± 118 to 337 ± 106, P = 0.012). TR reduction in amyloidosis patients was less extensive compared with that in control group (TR‐reduction 1.6 ± 0.3, P = 0.008 vs. control group 2.3 ± 0.3, P < 0.0001). Furthermore, these patients showed no significant improvement of structural right heart parameters. Conclusions: Transcatheter tricuspid valve repair is a safe and feasible new treatment option in patients with amyloid cardiomyopathy and has the potential to improve TR‐grade and clinical status. However, the benefit appears to be less pronounced compared with patients without cardiac amyloidosis. [ABSTRACT FROM AUTHOR]

Objective: To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes. Methods: Twenty‐five patients with symptomatic ATTRv‐PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age‐/sex‐matched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three‐dimensional gradient echo sequences with and without an off‐resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off‐resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off‐resonance saturation pulse. Subsequently, the MTR and cross‐sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv‐PNP patients and mutTTR‐carriers. Results: Sciatic nerve MTR and CSA reliably differentiated between ATTRv‐PNP, mutTTR‐carriers, and controls. MTR was lower in ATTRv‐PNP (26.4 ± 0.7; P < 0.0001) and in mutTTR‐carriers (32.6 ± 0.8; P = 0.0005) versus controls (39.4 ± 2.1), and was also lower in ATTRv‐PNP versus mutTTR‐carriers (P = 0.0009). MTR correlated negatively with the NIS‐LL and positively with CMAPs and SNAPs. CSA was higher in ATTRv‐PNP (34.3 ± 1.7 mm3) versus mutTTR‐carriers (26.0 ± 1.1 mm3; P = 0.0005) and versus controls (20.4 ± 1.2 mm3; P < 0.0001). CSA was also higher in mutTTR‐carriers versus controls. Interpretation: MTR is a novel imaging marker that can quantify macromolecular changes in ATTRv‐PNP and differentiate between symptomatic ATTRv‐PNP and asymptomatic mutTTR‐carriers and correlates with electrophysiology. [ABSTRACT FROM AUTHOR]

Abstract: Amyloidomas are rare amyloid‐containing lesions, which may also occur in the central nervous system. Etiology, pathogenesis and clinical course are poorly understood. To gain more insight into the biology of cerebral amyloidoma, they aimed to characterize its histopathological, molecular and clinical features in a retrospective series of seven patients. FFPE tissue specimens were examined using immunohistochemistry, chromogenic in situ hybridization (CISH) for light chains kappa and lambda as well as an IgH gene clonality analysis. Follow‐up information was gathered by reviewing patient records and imaging results. Median age of the three males and four females was 50 years (range: 35–53 years). All cerebral amyloidomas were located supratentorially and were classified as lambda light chain amyloidosis (AL‐λ; n = 6) and kappa light chain amyloidosis (AL‐κ; n = 1) on immunohistochemistry and CISH. B‐cell clonality was confirmed by IgH gene clonality assay in all cases examined. After a median follow‐up of 21 months, all patients were alive and showed stable disease. No progression to systemic disease was observed. In conclusion, their data suggest that cerebral amyloidoma is a local disease characterized by B‐cell clonality and associated with a stable clinical course. [ABSTRACT FROM AUTHOR]

Systemic amyloid light chain ( AL) amyloidosis is a life-threatening protein deposition disorder; however, effective therapy can dramatically improve the prognosis of AL patients. Therefore, accurate diagnosis of the underlying hematologic disease is important. Multi-parameter flow cytometry ( MFC) is a reliable method to analyze lymphatic neoplasias and to detect even a small lymphatic clone. We analyzed the presence of clonal plasma cell ( PC) and B cells in the bone marrow of 63 patients with newly diagnosed AL amyloidosis by MFC. We compared the results with the levels of monoclonal protein, the histopathology and cytogenetic results. As reference of light chain restriction, we used the immunohistochemical results of κ or λ positive amyloid deposits in various tissues. MFC identified underlying clonal lymphatic cells in all but two patients (61 of 63, 97%). Sixty-one patients harbored malignant PCs, whereas B-cell lymphomas were identified in two patients. Furthermore, MFC indicated at least one putative immunotherapeutical target ( CD20, CD38, CD52, or SLAMF7) on malignant PCs in all but one patient. These results demonstrate that MFC is a reliable tool for an accurate diagnosis of the underlying hematologic disease and the detection of potential immunotherapeutical targets in patients with AL amyloidosis. [ABSTRACT FROM AUTHOR]

Aims: The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Patients with cardiac amyloidosis (CA) have increased mortality. Aims: Clinical, electrocardiographic, and echocardiographic parameters were assessed for risk-stratification of CA. Methods and results: CA was confirmed by endomyocardial biopsy in 59 patients (54.8±1.2 years) with light-chain (n = 43) or transthyretin amyloidosis (n = 16). Six patients without CA served as controls (NCA). Clinical symptoms, electrocardiographic, and echocardiographic parameters were analyzed for prognostic significance. Of the patients with light-chain amyloidosis, 14 died and 2 underwent heart transplantation. 1-/3-year survival was 68%/63%. Survival depended on left ventricular function (LV-EF), LV mass, radius/wall thickness, septum thickness, low voltage pattern (LVP), conduction delay, NYHA class, and stem cell transplantation. A multivariate model only contained LV-EF and LVP; the beneficial effect of stem cell transplantation was cancelled out as this treatment was withheld in patients with highest cardiac risk. Survival was most limited if both risk factors occurred. Cardiac involvement in transthyretin amyloidosis showed better survival (2 deaths, 1-/3-year survival 91%/83%). Analysis of prognostic risk factor utility in all amyloid patients (light-chain and transthyretin) again revealed LVP and LV-EF, and aetiology of amyloidosis as independent survival parameters. Conclusion: Prognosis of CA is poor, but aetiology of amyloid, LVP, and LV-EF allows identification of patients at highest risk of death, who may require individual treatment approaches (heart transplantation prior to causative therapy). [Copyright &y& Elsevier]

Objective: To report 8 patients with Sjögren's syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases., Methods: The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated., Results: Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American-European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30-61 years) and amyloid had been diagnosed at a median age of 60 years (range 42-79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain-restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years., Conclusion: SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS.