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Copyright of Die Nephrologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. It arises from mutational changes in immunoglobulin light chains. To explore whether these mutations may affect the structure of the formed fibrils, we determine and compare the fibril structures from several patients with cardiac AL amyloidosis. All patients are affected by light chains that contain an IGLV3-19 gene segment, and the deposited fibrils differ by the mutations within this common germ line background. Using cryo-electron microscopy, we here find different fibril structures in each patient. These data establish that the mutations of amyloidogenic light chains contribute to defining the fibril architecture and hence the structure of the pathogenic agent. Systemic AL amyloidosis is one of the most frequently diagnosed forms of systemic amyloidosis. Here the authors analyse the structures of AL amyloid fibrils with different light chain mutations and show that the mutations contribute to defining the fibril structure in different patients. [ABSTRACT FROM AUTHOR]

Copyright of Die Kardiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Innere Medizin (2731-7080) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA. [ABSTRACT FROM AUTHOR]

Systemic light-chain (AL) amyloidosis is a rare and debilitating disease. Advances have been made in new treatments in recent years, yet real-world data on the management of the disease are scarce. EMN23 is a retrospective, observational study of patients who initiated first-line treatment in 2004–2018 in Europe, presenting the demographics, clinical characteristics, treatment patterns, and outcomes, from 4480 patients. Regimens based on bortezomib were the most frequently used as first-line therapy; only 6.2% of the patients received autologous stem cell transplant. Hematologic responses improved post-2010 (67.1% vs 55.6% pre-2010). The median overall survival (OS) was 48.8 (45.2–51.7) months; 51.4 (47.3–57.7) months pre-2010 and 46.7 (41.3–52.2) months post-2010. Early mortality was 13.4% and did not improve (11.4% vs 14.4% pre- and post-2010); furthermore, it remained high in patients with advanced cardiac disease (over 39% for stage IIIb). There was a significant improvement for stage IIIa (14.2 vs 30.7 months, p = 0.0170) but no improvement for stage IIIb patients (5.0 vs 4.5 months). This European real-world study of AL-amyloidosis emphasizes the unmet needs of early diagnosis, and the lack of improvement in survival outcomes of the frail stage IIIb population, despite the introduction of new therapies in recent years. [ABSTRACT FROM AUTHOR]

Wild type transthyretin-derived amyloid (ATTRwt) is the major component of non-hereditary transthyretin amyloidosis. Its accumulation in the heart of elderly patients is life threatening. A variety of genetic variants of transthyretin can lead to hereditary transthyretin amyloidosis, which shows different clinical symptoms, like age of onset and pattern of organ involvement. However, in the case of non-hereditary transthyretin amyloidosis ATTRwt fibril deposits are located primarily in heart tissue. In this structural study we analyzed ATTRwt amyloid fibrils from the heart of a patient with non-hereditary transthyretin amyloidosis. We present a 2.78 Å reconstructed density map of these ATTRwt fibrils using cryo electron microscopy and compare it with previously published V30M variants of ATTR fibrils extracted from heart and eye of different patients. All structures show a remarkably similar spearhead like shape in their cross section, formed by the same N- and C-terminal fragments of transthyretin with some minor differences. This demonstrates common features for ATTR fibrils despite differences in mutations and patients. This manuscript reports the structure of a pathologically relevant wild type ATTR amyloid fibril from systemic non-hereditary transthyretin amyloidosis. The comparison of the wild type ATTR fibril with two previous published ex vivo V30M ATTR fibrils highlighted numerous similarities between these different reconstructions, pointing to a common underlying structure for ATTR fibrils despite coming from different mutants and patients. [ABSTRACT FROM AUTHOR]

Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with light chain (AL) amyloidosis who survive longer albeit with end-stage renal disease. There is a critical need to identify patients in this population who benefit from renal transplantation. This multicenter, observational study from five countries includes 237 patients with AL amyloidosis who underwent renal transplantation between 1987 and 2020. With a median follow-up of 8.5 years, the median overall survival from renal transplantation was 8.6 years and was significantly longer in patients with complete and very good partial hematologic responses (CR + VGPR) compared to less than VGPR (9 versus 6.8 years; HR: 1.5, P = 0.04 [95% CI: 1–2.1]) at renal transplantation. Median graft survival was 7.8 years and was better in the CR + VGPR group (8.3 vs 5.7 years, HR: 1.4, P = 0.05 [95% CI: 1–2]). The frequency and time to amyloid recurrence in the graft was also lower (16% vs 37%, p = 0.01) and longer (median time not achieved vs 10 years, p = 0.001) in the CR + VGPR group. Comparing CR vs. VGPR there was no difference in overall or graft survival. Although 69 patients (29%) experienced hematologic relapse, treatment effectively prevented graft loss in the majority (87%). Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation. [ABSTRACT FROM AUTHOR]

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body. Systemic AL amyloidosis is caused by misfolding of immunoglobulin light chains (LCs) but how post-translational modifications (PTMs) of LCs influence amyloid formation is not well understood. Here, the authors present the cryo-EM structure of an AL amyloid fibril derived from the heart tissue of a patient that is partially pyroglutamylated, N-glycosylated and contains an intramolecular disulfide bond. Based on their structure and biochemical experiments the authors conclude that the mutational changes, disulfide bond and glycosylation determine the fibril protein fold and that glycosylation protects the fibril core from proteolytic degradation. [ABSTRACT FROM AUTHOR]

Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem. [ABSTRACT FROM AUTHOR]

Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p < 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43–1.30]; p < 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation. [ABSTRACT FROM AUTHOR]

The aggregation of antibody light chains is linked to systemic light chain (AL) amyloidosis, a disease where amyloid deposits frequently affect the heart and the kidney. We here investigate fibrils from the λ-III FOR005 light chain (LC), which is derived from an AL-patient with severe cardiac involvement. In FOR005, five residues are mutated with respect to its closest germline gene segment IGLV3-19 and IGLJ3. All mutations are located close to the complementarity determining regions (CDRs). The sequence segments responsible for the fibril formation are not yet known. We use fibrils extracted from the heart of this particular amyloidosis patient as seeds to prepare fibrils for solid-state NMR. We show that the seeds induce the formation of a specific fibril structure from the biochemically produced protein. We have assigned the fibril core region of the FOR005-derived fibrils and characterized the secondary structure propensity of the observed amino acids. As the primary structure of the aggregated patient protein is different for every AL patient, it is important to study, analyze and report a greater number of light chain sequences associated with AL amyloidosis. [ABSTRACT FROM AUTHOR]

Objectives: Direct toxic effects of transthyretin amyloid in patient plasma upon cardiomyocytes are discussed. However, no data regarding the relevance of this putative effect for clinical outcome are available. In this monocentric prospective study, we analyzed cellular hypertrophy after phenylephrine stimulation in vitro in the presence of patient plasma and correlated the cellular growth response with phenotype and prognosis. Methods and results: Progress in automated microscopy and image analysis allows high-throughput analysis of cell morphology. Using the InCell microscopy system, changes in cardiomyocyte's size after treatment with patient plasma from 89 patients suffering from transthyretin amyloidosis and 16 controls were quantified. For this purpose, we propose a novel metric that we named Hypertrophic Index, defined as difference in cell size after phenylephrine stimulation normalized to the unstimulated cell size. Its prognostic value was assessed for multiple endpoints (HTX: death/heart transplantation; DMP: cardiac decompensation; MACE: combined) using Cox proportional hazard models. Cells treated with plasma from healthy controls and hereditary transthyretin amyloidosis with polyneuropathy showed an increase in Hypertrophic Index after phenylephrine stimulation, whereas stimulation after treatment with hereditary cardiac amyloidosis or wild-type transthyretin patient plasma showed a significantly attenuated response. Hypertrophic Index was associated in univariate analyses with HTX (hazard ratio (HR) high vs low: 0.12 [0.02–0.58], p = 0.004), DMP: (HR 0.26 [0.11–0.62], p = 0.003) and MACE (HR 0.24 [0.11–0.55], p < 0.001). Its prognostic value was independent of established risk factors, cardiac TroponinT or N-terminal prohormone brain natriuretic peptide (NTproBNP). Conclusions: Attenuated cardiomyocyte growth response after stimulation with patient plasma in vitro is an independent risk factor for adverse cardiac events in ATTR patients [ABSTRACT FROM AUTHOR]

Patients who developed sepsis had higher median EASIX values before conditioning (EASIX-pre) and at any later time point until day+28 irrespective of pathogen detection (Fig. Using this cut-off for multivariable Cox regression analysis in the validation cohort, we observed a cause-specific HR of 16.1 (7.0-36.9) for EASIX > 2.32 with respect to time to sepsis, corresponding to 7/462 sepsis events (1.5%) in the low-risk group vs 40/172 (23%) in the high-risk group (Suppl. 1 A Box plot comparison of EASIX before and after alloSCT in patients who did or did not develop sepsis within 50 days after transplantation (full cohort). [Extracted from the article]

Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms. Systemic AL amyloidosis is a protein misfolding disease caused by the aggregation and fibrillation of immunoglobulin light chains (LCs). Here, the authors present the cryo-EM structures of λ3 LC-derived amyloid fibrils that were isolated from patient tissue and they observe structural breaks, where the two different fibril structures co-exist at different z-axial positions within the same fibril. [ABSTRACT FROM AUTHOR]

Background: Cardiac amyloidosis, caused by deposition of immunoglobulin light chains (AL) or transthyretin (ATTR), carries a poor prognosis. Established risk scores for amyloidosis may not predict outcomes in those patients who develop advanced heart failure and who are potential candidates for heart transplantation. Here, we aimed to identify predictive parameters for patients with severe heart failure due to amyloidosis. Methods: Out of > 1000 patients with cardiac amyloidosis (AL or ATTR) admitted to our centre between September 1998 and January 2016, a cohort of 120 patients with a complete cardiac assessment at diagnosis, including right heart catheterization, echocardiography and biomarkers, was analysed retrospectively in this study. Primary endpoint was all-cause mortality. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in AL and ATTR amyloidosis and compared those to established risk models for amyloidosis. Results: In the Cox multivariate model, high-sensitivity troponin T (hsTnT; hazard ratio (HR) 1.003; confidence interval (CI) 1.001–1.005; p = 0.009) and mean pulmonary artery pressure (HR 1.061; CI 1.024–1.100; p = 0.001) were found to significantly and independently predict outcomes for AL amyloidosis, whereas QRS duration (HR 1.021; CI 1.004–1.039; p = 0.013), hsTnT (HR 1.021; CI 1.006–1.036; p = 0.006) and N-terminal pro-brain natriuretic peptide (HR 1.0003; CI 1.0001–1.0004; p = 0.002) were the best predictors for ATTR amyloidosis. A simple risk score ("HeiRisk") including these parameters for AL and ATTR allowed a more precise risk stratification in our patient population compared to established risk models. Conclusions: Risk stratification for cardiac amyloidosis with the newly developed "HeiRisk" score may be superior to other staging systems for patients with advanced heart failure due to amyloid cardiomyopathy. [ABSTRACT FROM AUTHOR]

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Carpal tunnel syndrome (CTS) and spinal canal stenosis can be frequently observed in the medical history of patients with transthyretin amyloidosis (ATTR), both in the hereditary (mt-ATTR) and wild-type (wt-ATTR) form. The aim of this retrospective single-center analysis was to determine the prevalence of these findings, delay to diagnosis of systemic amyloidosis and the prognostic value in a large cohort of patients with wt-ATTR and mt-ATTR amyloidosis. Methods: Medical records of 253 patients diagnosed with wt-ATTR, 136 patients with mt-ATTR and 77 asymptomatic gene carriers were screened for history of CTS and spinal canal stenosis and laboratory analysis, electrocardiography and echocardiographic results, respectively. Clinical follow-up was performed by phone assessment. Results: History of CTS was present in 77 patients (56%) with mt-ATTR, in 152 patients (60%) with wt-ATTR and even in 10 of the asymptomatic gene carriers (13%). Latency between carpal tunnel surgery and first diagnosis of systemic amyloidosis was significantly longer in wt-ATTR compared to mt-ATTR (117 ± 179 months vs. 66 ± 73 months; p = 0.02). In total, 36 patients (14%) with wt-ATTR and 7 patients (5%) with mt-ATTR had a history of clinically significant spinal canal stenosis. In the subgroup of mt-ATTR, patients with CTS had thicker IVS (19 ± 5 mm vs. 16 ± 5 mm, p < 0.05), higher LV mass index (225 ± 78 g vs. 193 ± 98 g, p < 0.05), lower Karnofsky index (78 ± 15% vs. 83 ± 17%, p < 0.05), and lower mitral annular plane systolic excursion (MAPSE; 9 ± 4 mm vs. 11 ± 5 mm, p < 0.05) compared to patients without CTS, whereas in wt-ATTR no significant differences could be observed. No significant difference in survival was observed between patients with and without CTS (wt-ATTR: 67 vs. 63 months, p = 0.45; mt-ATTR: 74 vs. 63 months, p = 0.60). A combination of CTS and spinal stenosis was present in 32 wt-ATTR patients (12%) and 3 mt-ATTR patients (2.2%). Conclusions: The prevalence of CTS is high and the latency between CTS surgery and diagnosis of amyloidosis is long among patients with wt-ATTR and mt-ATTR. CTS might be predictive for future occurrence of systemic (predominantly cardiac) ATTR amyloidosis. [ABSTRACT FROM AUTHOR]

Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity. [ABSTRACT FROM AUTHOR]

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88L265P-mutation. Taken together, we detected 27 (93%) cases of AL amyloidosis with an associated light chain restricted and predominantly molecularly clonal plasma cell population. Clinical data were available in 18 patients. Five patients suffered from systemic lymphoma and two from systemic AL amyloidosis. The remaining cases were classified as localized with regard to both, the AL amyloidosis and the light chain restricted plasma cell population. To the best of our knowledge, we herein present the largest cohort of AL amyloidosis associated with a light chain restricted and predominantly molecularly clonal plasma cell population, which we designate as a distinct disease entity: "AL amyloidosis with a localized B cell neoplasia of undetermined significance". [ABSTRACT FROM AUTHOR]

Immunoglobulin-derived light-chain (AL) amyloidosis of lungs and bronchi can appear as a systemic and a local form. While systemic AL amyloidosis may need haemato-oncological care, the localised form can be treated restrained. We re-evaluated 207 specimens of lungs and bronchi sent in for amyloid diagnostics. Amyloid was diagnosed by polarization microscopy using Congo red-stained tissue specimens and classified immunohistochemically. Histoanatomical amyloid distribution patterns were documented as well as additional histological findings. For 118 patients with AL amyloidosis, we retrieved clinical data. CT scan results were available from 59 patients. AL amyloidosis was the most common type (183 cases). ALλ was found in 141 and of ALκ in 27 cases. Fifteen cases were AL amyloid not otherwise specified. Twenty cases harboured transthyretin and three serum amyloid A derived amyloid. By correlation of histoanatomy, radiological and clinical data, amyloid was rarely in the initial differential diagnosis. Local AL amyloidosis often presented with a nodular pattern on CT scan and showed a significantly better disease-specific 10-year survival compared with systemic AL amyloidosis (96.0 vs. 51.9%). Localised and systemic pulmonary and bronchial AL amyloidosis are having a completely different prognosis. While CT scan might be indicative, histological and clinical assessment are mandatory to reach a proper diagnosis and guide patient care. [ABSTRACT FROM AUTHOR]

The role of autologous stem cell transplantation (autoSCT) as consolidating treatment for peripheral T-cell lymphoma (PTCL) is unsettled. The aim of this analysis was to investigate the impact of autoSCT in the upfront setting by intent-to-treat and to study salvage strategies after relapse. Retrospective follow-up of all patients aged 18-70 years and treated at our institution for ALK-PTCL diagnosed between 2001 and 2014. Of 117 eligible patients, diagnosis was PTCL-NOS in 34, ALCL ALK- in 31, AITL in 28, and other PTCL in 24 patients. Disregarding 20 patients who received first-line treatment externally, upfront autoSCT was not intended in 34 due to comorbidity, higher age, low IPI, physician's decision or unknown reasons (nITT), while intent-to-transplant (ITT) was documented in 63 patients. ITT was not associated with significant benefits for 5-year progression-free survival (PFS) and overall survival (OS) with 46 and 23% in the ITT group vs. 42 and 25% in the nITT group, even after multivariate adjustment for confounders. Altogether, 91 of all 117 patients relapsed or progressed. Thirty-one patients managed to proceed to salvage allografting and achieved a 5-year OS of 52%. In contrast, all 7 patients receiving salvage autoSCT relapsed and died, and only 3 of the 51 patients not eligible for SCT salvage survived. In this study, a significant benefit of intending first-line autoSCT over non-transplant induction in patients with ALK-PTCL did not emerge. Most patients fail first-line treatment and have a poor outlook if salvage alloSCT cannot be performed. [ABSTRACT FROM AUTHOR]

In this retrospective observational study, we investigated the histopathological and demographic characteristics of amyloid in gastrointestinal biopsies. From the Amyloid Registry Kiel, we retrieved all cases with amyloid in biopsies of the stomach, duodenum, small intestine, large intestine, and rectum submitted for tertiary referral between January 2003 and April 2013. Amyloid was identified by Congo red staining in combination with polarization microscopy and classified by immunohistochemistry. The TTR-genotype was assessed in 56 patients. Amyloid type was correlated with demographic patient characteristics. Six hundred sixty-three biopsies from 542 patients were retrieved. Amyloid was found in each biopsy as vascular and/or interstitial amyloid deposits. Biopsies were obtained from the colon [254 biopsies (38.3 %)], stomach, [153 (23.1 %)], rectum [112 (16.9 %)], duodenum [105 (15.8 %)], and jejunum/ileum [39 (5.9 %)]. ALλ amyloid was found in 286 (52.8 %), ATTR in 88 (16.2 %), ALκ in 74 (13.7 %), AA in 58 (10.7 %), and ApoAI amyloid in 4 (0.7 %) patients. The remaining 21 cases were ALys amyloid in 4 (0.7 %), AL n.o.s. in 14 (2.6 %), and mixed type amyloidosis in 3 (0.6 %). The amyloid of 11 (2.0 %) cases remained unclassified. The median age of the patients was 68 years. Men [332 (61.7 %)] were significantly more prevalent than women [206 (38.3 %); p < 0.001]. TTR mutations were found in 24 % of the patients with ATTR amyloidosis. The median age, the histoanatomical distribution (proximal to distal; mucosal to submucosal), and the deposition pattern (vascular/interstitial) varied between different amyloid types. Amyloid in gastrointestinal biopsies mainly affects male elderly patients and shows amyloid-type-specific demographic patient characteristics. [ABSTRACT FROM AUTHOR]

Correction to: Allogeneic hematopoietic stem cell transplantation improves long-term outcome for relapsed AML patients across all ages: results from two East German Study Group Hematology and Oncology (OSHO) trials A Overall survival (OS) of patients with AML after frst relapse according to age. C Overall survival (OS) of patients with AML after frst relapse according to favorable, intermediate, and unfavorable cytogenetics. [Extracted from the article]

Background: Vascular amyloid deposition is common in light-chain amyloidosis resulting in endothelial dysfunction. Human placental growth factor (PlGF), a member of the vascular endothelial growth factor family was found to be altered in diverse pathological conditions, e.g. endothelial dysfunction. This study evaluated the clinical role of PlGF in light-chain amyloidosis. Methods: PlGF (cobas-PlGF, Roche Diagnostics, Mannheim, Germany) was analyzed in 125 consecutive patients with AL and correlated with diverse clinical parameters including mortality. Results: Kidney ( n = 76) and heart ( n = 57) were predominantly affected by amyloid deposition. Median PlGF was 26.3 (21.1-42.1) ng/L, NT-proBNP 3649 (1124-8581) pg/mL, and hs-TnT 42 (21-107) ng/L. PlGF increased with number of organs involved and with deterioration of renal function. A significant correlation of PlGF with hs-TnT ( ρ = 0.306; p = 0.0007) and NT-proBNP ( ρ = 0.315; p = 0.0006) was observed, but no correlation was observed with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. In this cohort 1-year all-cause mortality was 19.2 %. The best cutoff discriminating survivors and non-survivors was 28.44 ng/L (sensitivity 66.7 %; specificity 78.1 %). A three-step risk model including hs-TnT and NT-proBNP revealed a better discrimination if patients at intermediary risk were additionally stratified by PlGF. Net reclassification index was 37.2 % ( p = 0.002). Multivariate analysis revealed PlGF, difference of involved and uninvolved light chain, number of organs involved and risk class according to troponin T and NT-proBNP as independent predictors of mortality. Conclusion: Plasma PlGF values in AL are invariably associated with the number of involved organs, but not with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. PlGF provide useful information for risk stratification of patients at intermediary risk according to hs-TnT and NT-proBNP. [ABSTRACT FROM AUTHOR]

Hereditary thrombocythemia (HT) has been described as a rare benign disorder caused by mutations in the thrombopoietin (THPO) or the c-Mpl receptor genes. Here we report two families with HT resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects, whereas in the other one member developed early-onset multiple myeloma. These observations, together with previously reported patients, suggest that THPO gain of function may dysregulate the hemangioblast and disturb vasculogenesis and hematopoietic development. Overstimulation of the THPO pathway might therefore predispose to clonal hematopoietic disease and to congenital abnormalities. [ABSTRACT FROM AUTHOR]

Background: Evaluation of left ventricular function (LV) is one of the most important tasks of echocardiography. Left ventricular longitudinal function has been recognized to differentiate myocardial disorders better than ejection fraction (EF) alone. But recent parameters are still dependent on image quality and time consuming. Methods: Transthoracic echocardiography, tissue Doppler imaging, strain imaging and assessment of longitudinal function with a tissue motion annular displacement (TMAD) tracking algorithm were performed in 152 patients with various cardiac pathologies and 47 healthy volunteers in a clinical routine setting. Results: Measures of longitudinal function such as LV peak systolic strain (SR, r² = 0.88, p < 0.001) and peak systolic strain rate (SRR, r² = 0.78, p < 0.001) correlated highly with TMAD. Tissue motion annular displacement was ultrafast and less time-consuming compared to strain imaging (8.2 ± 2.2 s, p < 0.001). Significantly more patients with reduced image quality could be analyzed compared to strain imaging ( p < 0.001). The intra- and inter-observer variabilities were very low with 1.3 ± 1% and 1.7 ± 1.2%. Tissue motion annular displacement correlated well with clinical parameters (NYHA, r = −0.71, p < 0.001) as well as NT-proBNP ( r = −0.73, p < 0.001) and identified patients with structural heart disease with a significantly higher sensitivity 92.1% and specificity 95.7% than did EF, SR, SRR or NT-proBNP (Cut-off:14.2%, p < 0.01). In a subgroup of patients with systemic light chain amyloidosis and preserved EF (>50%, n = 54), TMAD was significantly reduced, especially in those without any signs of cardiac involvement and was superior to other parameters of longitudinal function ( p < 0.05). Conclusions: Tissue motion annular displacement is a rapid, sensitive and reproducible method for the assessment of LV longitudinal function, which is less dependent on image quality. [ABSTRACT FROM AUTHOR]

The prognosis of cardiac amyloidosis depends on the nature and origin of the amyloid protein deposited. However, little is known about the prevalence and origin of amyloid in heart muscle biopsies. We therefore examined retrospectively the distribution and origin of amyloid in a consecutive series of endomyocardial biopsies. Endomyocardial biopsies with verified presence of amyloid from 101 patients were included. Amyloid was classified immunohistochemically in each of them. Our collective comprised 63 men and 38 women, with a mean age of 66 years (range 37-85 years). Cardiac amyloidosis was the most common of the AL (54 patients) or ATTR type (42 patients). In five individuals, amyloid remained unclassified. AL amyloidosis was subdivided into ALlambda (45 patients) and ALkappa amyloid (nine patients). AA amyloid was not found in any individual. The amount of amyloid was higher in AL than in ATTR amyloidosis. Genomic DNA was extracted and examined by DNA sequencing in 19 patients with ATTR amyloidosis. Five (26%) individuals carried TTR mutations (p.Val20Ile, p.Val30Met (twice), p.Asp39Val and p.Glu54Asp) and were classified as suffering from hereditary ATTR amyloidosis. Amyloid in endomyocardial biopsies is most commonly of immunoglobulin light chain origin, followed by non-hereditary and hereditary-type ATTR amyloid. [ABSTRACT FROM AUTHOR]

The immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with multiple myeloma (MM). Their efficacy is increased with the addition of dexamethasone, but significant rates of venous thromboembolism (VTE) are a severe side effect. Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients. However, the optimal prophylaxis remains controversial. We analyzed 45 patients with relapsed MM who were treated with lenalidomide and dexamethasone at our center. The 45 patients received a total number of 192 cycles, respectively a median of three cycles; the median dosage of dexamethasone was 240 mg per cycle. All patients received prophylactic anticoagulation with low molecular weight heparin (LMWH). Moreover, 86.6% of patients had at least one additional VTE risk factor beside the myeloma-related risk. One out of 45 patients developed a deep vein thrombosis and pulmonary embolism. None of the other 44 patients had clinical signs of thrombosis or embolism and none of all patients experienced complications or side effects due to anticoagulation. Our results indicate that prophylactic anticoagulation with LMWH is safe and effective. Therefore, we propose LMWH should be used in patients being treated with lenalidomide and dexamethasone at least for the first 3 months of treatment until randomized trials have proven the equality of other pharmacological prophylaxis. [ABSTRACT FROM AUTHOR]

Plasma protein fibrinogen variants cause fibrinogen A alpha-chain (AFib) amyloidosis, which presents with hypertension, proteinuria, and azotemia. Six AFib mutations have been reported thus far. We identified three patients who presented with marked proteinuria and serum creatinine elevations. Their kidney biopsies revealed destruction of the glomerular architecture by amyloid deposits with typical, apple-green birefringence in polarized light after Congo red staining. We found immunoreactivity against fibrinogen, which is typical for this type of amyloidosis. We sequenced the FGA exon 5 and demonstrated heterozygosity for the p.Glu526Val mutation in all three cases. This amino acid substitution is the most common fibrinogen A alpha-chain variant causing AFib amyloidosis. The mutation has been reported in individuals of European and American descent but not yet in German patients. AFib amyloidosis should therefore be considered an important differential diagnosis in German patients with renal amyloidosis. In the cases described here, the use of antibodies directed against fibrinogen, followed by direct gene sequencing, revealed the underlying cause. [ABSTRACT FROM AUTHOR]

Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradi ation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n = 48; marrow graft, n = 15). Diagnoses included multiple myeloma (n = 61), myelodysplastic syndrome (n = 55), chronic myeloid leukemia (n = 31), non-Hodgkin lymphoma (n = 31), acute myeloid leukemia (n = 28), chronic lymphocytic leukemia (n = 24), Hodgkin Disease (n = 14). The conditioning regimen was fludarabine 30 mg/m2/d x 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil an cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100-1,188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projecte 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100-468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients, 54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse. Related and unrelated nonmyeloablative HSCT is feasible and potentially curative in patients with advanced hematological malignancies who have no other treatment options. [ABSTRACT FROM AUTHOR]