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Background and Aims The aims of this study were to assess prescription patterns, dosages, discontinuation rates and association with prognosis of conventional heart failure (HF) medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). Methods A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000-2022 identified 2371 patients with ATTR-CA. Results Prescription of HF medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-II receptor blockers (ARB) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (IQR 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARB discontinued. In contrast, only 7.5% had MRAs discontinued. Propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population (HR 0.77 [95% CI 0.66-0.89], P40% (HR 0.75 [95% CI 0.63-0.90], P=0.002); and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% (HR 0.61 [95% CI 0.45-0.83], P=0.002). No convincing differences were found for treatment with ACEi/ARBs. Conclusions Conventional HF medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Aims To assess the ability of cardiovascular magnetic resonance (CMR) to (i) measure changes in response to chemotherapy; (ii) assess the correlation between haematological response and changes in extracellular volume (ECV); and (iii) assess the association between changes in ECV and prognosis over and above existing predictors. Methods and results In total, 176 patients with cardiac AL amyloidosis were assessed using serial N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography, free light chains and CMR with T1 and ECV mapping at diagnosis and subsequently 6, 12, and 24 months after starting chemotherapy. Haematological response was graded as complete response (CR), very good partial response (VGPR), partial response (PR), or no response (NR). CMR response was graded by changes in ECV as progression (≥0.05 increase), stable ( Conclusions Cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR. Changes in ECV predict outcome after adjusting for known predictors.

ObjectivesIn AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy.MethodsThis study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012–2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter.ResultsIn total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (pConclusionThe 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.

Aims To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. Methods and results A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. Conclusion The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Most haemodialysis machines deliver a fixed bicarbonate concentration. Higher concentrations may improve acidosis, but risk post-haemodialysis alkalosis, whereas lower concentrations potentially increase acidosis but reduce alkalosis. We reviewed the effects of lowering dialysate bicarbonate.We reviewed peri-dialysis chemistries in patients switching to a lower bicarbonate dialysate at 4 time points over 19 months.We studied 126 patients, mean age 63.7±16.3 years, 57.9% males. Post-haemodialysis alkalosis fell from 1.6 to 0.3% sessions, but pre-haemodialysis acidosis increased from 11.9 to 23.8% sessions (p=0.005) reducing dialysate bicarbonate from 32 to 28 mmol/L. After 3 months, pre-haemodialysis serum bicarbonate fell (21.1±2.3 to 19.8±2.2 mmol/L), and post-haemodialysis (24.9±2.1 to 22.5±2.0 mmol/L, p0.001 with a fall in pre-haemodialysis weight from 74.6±20.7 to 71.7±18.2 kg, normalised protein nitrogen accumulation rate 0.8±0.28 to 0.77±0.2 g/kg/day, p0.05, and serum albumin 39.7±4.2 to 37.7±4.9 g/L, p0.001. Thereafter, apart from pre- and post-haemodialysis serum bicarbonate, weight and normalised protein nitrogen accumulation stabilised, although albumin remained lower (37.6±4.0 g/L, p0.001). On multivariate logistic analysis, serum bicarbonate increased more with lower pre-haemodialysis bicarbonate standardised coefficient β 0.5 (95% confidence interval -0.6 to -0.42), increased normalised protein nitrogen accumulation β 0.2 (0.96 to 2.38), p0.001, and session time β 0.09, (0.47to 5.98), p0.022, and less with lower dialysate bicarbonate 0-.23 (-1.54 to -0.74), p0.001.Increases in SE-Bic with haemodialysis, depend on the bicarbonate gradient, session time and nPNA. Lower D-Bic reduces post-haemodialysis alkalosis but increases pre-haemodialysis acidosis and may initially have adverse effects on weight and normalised protein nitrogen accumulation.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

ObjectivesWild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM.MethodsThis is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression.ResultsChange in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively.ConclusionChange in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations.We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019.In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0-31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg,AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent.

BackgroundOutcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes.MethodsWe performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan–Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses.ResultsOne-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P 12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes.ConclusionsRenal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Hematopoietic stem cell transplantation (HSCT) is increasingly used as first-line management in adults with aplastic anaemia even in the absence of a sibling donor. HSCT can be associated with a broad range of acute and chronic complications, including infections, graft versus host disease, and other immune complications. Renal complications are common following HSCT, including acute kidney injury (10%–70%), chronic kidney disease (7%–48%), and thrombotic microangiopathy and nephrotic syndrome (0.4%–4%).1 In addition, renal manifestations of both acute and chronic graft versus host disease (GvHD) have been described, including nephrotic syndrome, which usually occurs as a late complication most commonly due to membranous nephropathy.2, 3, 4 Post-transplant lymphoproliferative disorder (PTLD) post HSCT occurs in up to 3.2% of allogeneic transplant recipients and is almost exclusively Epstein-Barr virus (EBV) related.5 Management includes reduction of immunosuppression, rituximab, and/or chemotherapy in higher risk disease. Minimal change disease (MCD) complicates Hodgkin disease in approximately 0.4%, and less commonly non-Hodgkin lymphoma.6,7 We present, to our knowledge, the first reported case of MCD associated with EBV-driven PTLD following HSCT and demonstrate an excellent response to rituximab with remission of nephrotic syndrome, normalization of Epstein-Barr viremia, and full clinical remission of PTLD.

Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course. Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P

We report a case in which a renal transplant recipient with metastatic melanoma had an excellent response to treatment with second line programmed cell death protein 1 (PD-1) inhibitor therapy, pembrolizumab. Acute cellular allograft rejection on initiation of PD-1 inhibitor was successfully reversed with methylprednisolone. By converting the patient to sirolimus and giving predose prednisolone, pembrolizumab was continued with stable renal function and an excellent oncological response. This case supports the efficacy of PD-1 inhibitors in patients who are chronically immunosuppressed, and suggests an approach to maintain transplant function.

Background: Daratumumab is a monoclonal antibody, which targets CD38; an antigen expressed on malignant plasma cells in AL amyloidosis thus providing a rationale for its use.Method: Patients treated with daratumumab monotherapy (2016-2019) for relapsed/refractory systemic AL amyloidosis were identified from the database at the UK National Amyloidosis Centre.Results: Of 50 evaluable patients, haematological responses at 3 months were: CR - 19 (38%), VGPR - 14 (28%), PR - 9 (18%) and no response - 8 (16%). Median time to response was 1 (1-6) month. Of assessable patients, cardiac, renal and hepatic responses were seen in 43.8%, 25.0% and 0% of patients whilst progression occurred in 25.0%, 12.5% and 37.5% respectively. Patients achieving a CR had longer median OS (not reached vs. 22.7 months [95% CI 17.0-28.4 months]) (p = .036). Furthermore, patients achieving a rapid response (at 1 month) had a longer median PFS (not reached vs. 9 months [95% CI 5.8-12.2 months]) (p = .013).Conclusion: Daratumumab monotherapy is effective in multiply-relapsed systemic AL amyloidosis and should be considered, if available, in patients who have not received prior daratumumab therapy. Responses are achieved rapidly and overall response rate was 84%. CR predicts overall survival whilst speed of response is predictive of a longer PFS.

The majority of peritoneal dialysates use glucose to generate an osmotic gradient for the convective removal of water and Na. Although glucose can potentially be absorbed, previous studies have failed to establish whether this leads to increased fat weight gain. We measured body composition using bioimpedance in peritoneal dialysis (PD) patients, electively starting PD, attending for their first assessment of peritoneal membrane function after 2–3 months, and then after 12 months. We studied 143 patients: eighty-nine (62·2 %) males, fifty-three (37·1 %) diabetics, mean age 61·3 (SD14·9) years, with ninety (62·1 %) patients treated by automated PD cyclers with a daytime icodextrin exchange and thirty-seven (25·9 %) by continuous ambulatory PD. Median fat mass increased by 1·8 (–0·5 to 4·1) kg, whereas fat-free mass fell –1·3 (–2·9 to 1·0) kg, and the increase in fat mass was negatively associated with the fall in soft lean mass (r–0·41,P< 0·001). Increased fat mass was associated with measured peritoneal glucose absorption (r0·69,P< 0·001), and glucose absorption was associated with the amount of 22·7 g/l glucose dialysate (OR 2·0, 95 % CI 1·5, 2·5,P< 0·001), peritoneal urea clearance (OR 9·5, 95 % CI 2·4, 37·1,P= 0·001) and male sex (OR 4·8, 95 % CI 1·5, 14·9,P= 0·008). We report an observational study in prevalent PD patients following body composition from their first assessment of PD membrane function for approximately 12 months, and despite the majority of patients prescribed icodextrin, we have demonstrated not only an association between intra-peritoneal glucose absorption and fat weight gain but also loss of fat-free mass.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM; this equates to 1.6 million carriers in the USA. We report deep phenotyping in p.V142I ATTR-CM. Hypothesis: The phenotype of p.V142I ATTR-CM is an aggressive form of ATTR CM. Methods: A retrospective study of 395 patients with p.V142I ATTR-CM from the UK National Amyloidosis Centre. Patients were diagnosed at the Centre through a comprehensive evaluation comprising clinical and functional assessment, echocardiography, radionuclide scintigraphy, histology and biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild-type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of diagnosis) were used as a comparator group. Results: At time of diagnosis, patients with p.V142I ATTR-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38.2%) and impairment of echocardiographic parameters; mean LVEF 43%, global longitudinal strain -9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid (51%) regurgitation. Uni and multivariate cox regression analysis identified troponin T, TR, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters and 5yr survival (27% v 46%, p Conclusion: p.V142I ATTR-CM has an aggressive phenotype characterised by functional impairment, regurgitant valvular disease and systolic impairment resulting in poor survival. LV systolic impairment, TAPSE, serum troponin and TR were independent predictors of survival, whereas LV wall thickness was not, suggesting as yet unrecognised disease mechanisms.

Diagnoses of amyloidosis, particularly transthyretin amyloid cardiomyopathy (ATTR-CM), are steadily increasing throughout the world, but the condition remains underdiagnosed. Patients with amyloidosis may present to a range of medical and surgical specialties, often with multisystemic disease, and a high index of clinical suspicion is required for diagnosis. Bone scintigraphy and cardiovascular magnetic resonance (CMR) imaging offer highly sensitive and specific imaging modalities for cardiac amyloidosis. Histological confirmation of amyloid deposition and amyloid type remains the cornerstone of diagnosis for most amyloid types, with transthyretin amyloid cardiomyopathy the exception, which may be diagnosed by validated nonbiopsy diagnostic criteria in the majority. Histological diagnosis of amyloid has been enhanced by laser capture microdissection and tandem mass spectrometry. Early diagnosis and treatment prior to the development of end-organ damage remains essential to improving morbidity and mortality for patients with amyloidosis.

Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. Methods and results A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of 100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23–20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). Conclusion Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Diagnoses of amyloidosis are increasing annually, and advances in bone scintigraphy and cardiac MRI accompanied by development of nonbiopsy diagnostic criteria have specifically led to a huge increase in transthyretin amyloidosis cardiomyopathy (ATTR-CM) diagnoses worldwide. Tafamidis use is increasing, and there are several ongoing phase III clinical trials of novel agents that promise to transform the treatment landscape for patients with ATTR-CM. In systemic light chain (AL) amyloidosis, more effective chemotherapeutic agents continue to improve patient outcomes. Accelerating the removal of amyloid deposits to accompany these therapies remains the holy grail. However, in the meantime, early diagnosis is undoubtedly key in improving patient outcomes.

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Background: Systemic amyloidosis is characterized by amyloid deposition that can involve virtually any organ. Splenic and hepatic amyloidosis occurs in certain types, in some patients but not others, and may influence prognosis and treatment. SAP (serum amyloid P component) scintigraphy is uniquely able to identify and quantify amyloid in the liver and spleen, thus informing clinical management, but it is only available in 2 centers globally. The aims of this study were to examine the potential for extracellular volume (ECV) mapping performed during routine cardiac magnetic resonance to: (1) detect amyloid in the liver and spleen and (2) estimate amyloid load in these sites using SAP scintigraphy as the reference standard. Methods: Five hundred thirty-three patients referred to the National Amyloidosis Centre, London, between 2015 and 2017 with suspected systemic amyloidosis who underwent SAP scintigraphy and cardiac magnetic resonance with T1 mapping were studied. Results: The diagnostic performance of ECV to detect splenic and hepatic amyloidosis was high for both organs (liver: area under the curve, −0.917 [95% CI, 0.880–0.954]; liver ECV cutoff, 0.395; sensitivity, 90.7%; specificity, 77.7%; P P P P P P Conclusions: Our study demonstrates that ECV measurements obtained during routine cardiac magnetic resonance scans in patients with suspected amyloidosis can identify and measure the magnitude of amyloid infiltration in the liver and spleen, providing important clues to amyloid type and offering a noninvasive measure of visceral amyloid burden that can help guide and track treatment.

Continued improvement in the 3D NAND bit density is essential to satisfy the exponentially growing demand for data storage. The transition from 3b/cell (TLC) to 4b/cell (QLC) is a significant step towards delivering higher bit density. The increased program/erase (P/E) window, in 3D NAND technology, combined with improved program algorithms to alleviate interference from neighboring WL cells, has led to the successful deployment of two generations of QLC floating gate (FG) 3D NAND technology [1]. Further improvement in bit density, as well as the read and write performance will accelerate the adoption rate of QLC NAND into data-storage systems.

Aims Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients. Methods and results A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean −21.1%, −17.1%, −12.9%, and −12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤−16.2%: 80 months, −16.1% to −12.2%: 36 [95% confidence interval (CI) 20.9–51.1] months, −12.1% to −9.1%: 22 (95% CI 9.1–34.9) months, and ≥−9.0%: 5 (95% CI 3.2–6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from −13.8% to −14.9% in those with CR and difference between involved and uninvolved light chain Conclusion Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

Background Systemic Immunoglobulin light chain amyloidosis (AL) is a protein-misfolding disorder associated with an underlying monoclonal B-cell or plasma cell dyscrasia. There is little information on how response durability impacts outcomes. It is conceivable that early relapse may confer an adverse prognosis in AL, like in Myeloma. Here, we test the above hypothesis and analyse the factors affecting response durability in a cohort of AL patients treated with frontline Bortezomib. Methods All patients treated with frontline Bortezomib in 2010-2019 are included in the analysis. Patients with primary refractory disease, those with a continuing response but ≤ 24 months follow up, and those who received 2nd line therapy for reasons other than progression are excluded from the analysis. We defined early relapse (ER) as PFS ≤ 24 months. Results 560 patients are included in this analysis. 250 (44.6%) and 310 (55.4%) patients had ER and LR, respectively. The ER group had more advanced cardiac disease (p 20% (p=0.021), ≥ VGPR after 1st line (p 20%, and dFLC Conclusions In conclusion, these data identify a high-risk group of patients who relapse early and have a poorer survival (irrespective of their initial response). The depth of response to the initial treatment is a critical determinant of response durability. The early relapses should be considered for clinical trials that can identify treatments with the potential to overcome the high-risk biology of the disease.

Background The six-minute walk test (6MWT) is an easy-to-implement objective measure of functional capacity. This standardised reproducible measure of individual function may have value in systemic AL amyloidosis to provide an additional objective measure of fitness for chemotherapy, impact of chemotherapy and, within the clinical trial setting, both as a potential clinical endpoint and exclusion criteria. We aim to validate its prognostic value in AL amyloidosis. Methods All patients from a prospective observational study of newly diagnosed AL amyloidosis, (ALchemy) over a 5-year period, were studied. Six-minute walk testing was performed at baseline and 6, 12, 18, 24, 36 and 48-month follow up. Both the median 6MWT and percentage predicted for age, sex, height and weight were analysed. Results In total, 799 evaluable patients were included of whom 564 (70.6%) had cardiac involvement. Baseline 6MWT distance was 418.5 metres (m) / 80.5% predicted, and diminished with increasing cardiac Mayo stage (p Patients were followed up for a median of 32 (1-90) months following diagnosis. Median overall survival (OS) was 70.0 (56.8-83.2) months. The median OS of patients achieving ≥300m on baseline 6MWT was not reached whilst those achieving The 6MWT fell significantly by 6 months (391.0m/73.5%, p=0.0002) then rose again by 12 months (median 415.0m/78.0%, p=0.02). There was no significant change in 6MWT thereafter. When stratified by haematological response and censoring deaths before 12 months, only patients in a complete response (CR) improved at 12 months (431.0m/83.0% vs. 437.0m/85%, p=0.001) whilst those with a lesser haematological response got worse (Very good partial response [VGPR]: 403.5m/75.0% to 395.5m/76.5%, p=0.02; Partial Response [PR]: 413.0m/79.0% to 362.5m/74.0%, p=0.0007; Nil response [NR]: 437.0m/83.0% to 355.0m/70%, p=0.0002). A 33m improvement in 6MWT, a value reported to be clinically meaningful in cardiopulmonary disorders, was independent of haematological response in predicting survival (CR [reference], VGPR: HR 2.02 [1.08-3.80], p=0.03; PR: HR 3.51 [1.83-6.73], p Patients in whom 6MWT improved by ≥33m at 12 months survived longer although median OS was not reached in either category (p=0.01). In patients who achieved a baseline 6MWT of Conclusion The 6MWT is prognostic in AL amyloidosis at multiple time points and a baseline distance of ≥300m is independent of current Mayo stage criteria in predicting survival. Inability to undertake a 6MWT at baseline is an extremely poor prognostic indicator. At 12 months, improvement in 6MWT of ≥33m predicts survival independent of haematological response. The 6MWT is a useful prognostic indicator in systemic AL amyloidosis and could be used as an inclusion/exclusion criterion in the clinical trial setting. Disclosures Wechalekar: Celgene: Honoraria; Takeda: Honoraria, Other: Travel; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac involvement. Mayo stage I, II, IIIa and IIIb in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. Impairment of LS% correlated significantly with increasing Mayo stage (p Conclusion: Longitudinal strain is an informative functional marker that is independent of Mayo staging in predicting outcomes in patients with cardiac AL amyloidosis which can be incorporated in prognostic staging for these patients. Improvement in LS% was observed in patients who achieved a CR, and a value of 1.5% was associated with superior outcomes over and above achieving a cardiac response by international consensus criteria. An absolute improvement in LS% should be considered a criterion for cardiac response in AL amyloidosis. Disclosures Wechalekar: Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria.

The Prognostic Significance of Elevated Troponin Levels in Patients with Normal Coronaries Undergoing Surgery for Aortic Valve Steno Objective: The outcome of aortic valve replacement (AVR) in patients without occlusive coronary artery disease who present with raised pre-operative troponin is not clear. We therefore, investigated the operative mortality and morbidity in this subset of patients undergoing urgent surgery for aortic stenosis. Methods: From a pool of 595 AVR patients in our institution’s database from July 2007 to July 2013, we reviewed the notes of all patients who underwent urgent surgery for aortic stenosis (n=57) and identified those with raised pre-operative troponin (n=16). We compared the observed operative mortality and major morbidity rates between patients with raised preoperative troponin levels (group I) and those with normal troponin levels (group II), and also with their predicted outcomes. Results: The baseline and operative characteristics for the two groups were comparable. There was a trend towards higher operative mortality for group I patients (18.8% versus 7.3% for group II, P=.07). Whereas, the observed operative mortality for group I far exceeded the predicted (18.8% vs 12.5%, p=.05), for group II the observed was slightly lower than the predicted operative mortality (7.3% vs 9.3%, p=.63). On the other hand, the observed mortality was well below the predicted for the elective patients. Conclusion: Patients with aortic stenosis and raised preoperative troponin undergoing urgent AVR may be at risk of higher operative mortality than predicted by the EuroScore. Further studies in this high risk group are warranted.

The inventory, evaluation and treatment of cultural resources represent a significant challenge for siting and permitting natural gas pipelines. Project sponsors assist the Federal Energy Regulatory Commission’s Office of Energy Projects with meeting its obligations under Section 106 of the National Historic Preservation Act. The increasing sophistication of compliance with Section 106 is reflected in the Office of Energy Project’s 2002 Guidelines for Reporting on Cultural Resources Investigations for Pipeline Projects. Recent pipeline projects in the United States have involved environmental study corridors that are both wide and extensive, a combination that results in the identification of large numbers of cultural properties. The process of cultural resources management begins in the project planning stage with the development of site location modeling, analysis of previous investigations within or near Areas of Potential Effect, and consideration of the likelihood for encountering potentially eligible National Register of Historic Places properties. Using this information, site detection survey strategies can be developed that intensively target only sensitive portions of the Area of Potential Effect. During the survey, identification of archaeological sites, historic structures, or cultural landscapes requires prompt evaluation of National Register eligibility status for the purposes of avoidance or development of treatment plans. This presentation considers the Section 106 compliance process and how project sponsors can effectively manage cultural resources to ensure cost effectiveness and maintenance of restricted project schedules, while meeting the objectives of the National Historic Preservation Act.Copyright © 2008 by ASME