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David C Seldin - One of the best experts on this subject based on the ideXlab platform.
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ClinicAL presentation and treatment responses in IgM-related AL Amyloidosis
Amyloid, 2015Co-Authors: Moussa Sissoko, David C Seldin, John L. Berk, Vaishali Sanchorawala, Brian Sworder, Kenneth Angelino, Mike Broce, J. Mark SloanAbstract:Amyloid light-chain (AL) Amyloidosis is a multi-organ disease due to deposition of misfolded monoclonAL immunoglobulin light chains. IgM AL Amyloidosis is a rare variant, about 6% of AL Amyloidosis cases, and more data are needed for treatment guidance. In IgM AL Amyloidosis, the clonAL cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinicAL and laboratory features of 95 patients with IgM AL Amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% mALes. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinAL tract (17%). Treatment responses were anALyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. OverALl hematologic response rates and very good partiAL or complete hematologic response rates, respectively, were: high-dose melphALan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose ALkylating agents (MelphALan or cyclophosphamide) 63%;19%. OverALl, 5-year survivAL rates were significantly higher in patients with a hematologicAL response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typicALly expected in AL Amyloidosis.
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ClinicAL Presentation and Treatment Responses In IgM-Related AL Amyloidosis
Blood, 2013Co-Authors: Vaishali Sanchorawala, David C Seldin, John L. Berk, Brian Sworder, John Mark SloanAbstract:AL Amyloidosis is a multiorgan disease due to deposition of misfolded monoclonAL immunoglobulin light chains. AL Amyloidosis associated with IgM paraproteinemia is a rare variant of this disease, constituting approximately 6% of AL Amyloidosis cases in the literature. The clonAL cell of origin may be a plasma cell or a lymphoplasmacytic cell, and treatments targeting each of these populations have been employed. This study defines the clinicAL and laboratory characteristics of IgM-related AL Amyloidosis patients as well as their response to different therapeutic regimens. We identified 94 patients with IgM-related AL Amyloidosis evALuated at the BUMC Amyloidosis Center from 2003 through 2012 for which data was available on 50 who completed treatment. The median age at diagnosis was 65 years (range: 42-79 years) with 31 (62 %) mALes. The most commonly involved organ was the kidney (59%) followed by heart (37%) and GI tract (22%). The mean IgM was 1049 g/dL (range: 29-9130). The clonAL population had lambda light chain restriction in 34 (68%) of patients. Patients were categorized into 5 treatment groups: high-dose melphALan/stem cell transplant (HDM/SCT), bortezomib-based, non-transplant ALkylating agents based (melphALan or cyclophosphamide), immunomodulatory agents (IMiDs), and rituximab-based. This grouping was not mutuALly exclusive. The highest hematologic response rate was observed with HDM/SCT (10/10: 100%), followed by non-transplant ALkylating agents (16/22: 73%), bortezomib (7/10: 70%) rituximab (9/13: 69%) then by IMiDs (2/4: 50%). We did not observe an association between positive response to treatment and organ involvement, sex or age at diagnosis. In conclusion, IgM-related ALAmyloidosis is an unusuAL variant of AL Amyloidosis. Multiple active therapies with different mechanisms of action exist; treatment should be tailored based upon clinicopathologic and patient-specific factors. Disclosures: Sloan: Millenium: Consultancy.
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cancer testis antigen expression and immunogenicity in AL Amyloidosis
Blood Cancer Journal, 2012Co-Authors: Michael Rosenzweig, Denise Frosina, Heather Landau, David C Seldin, Saulius Girnius, Nicole Hanson, Christine Sedrak, Maria E Arcila, Carl Ohara, Raymond L ComenzoAbstract:Light-chain Amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of severAL CTAs in patients with AL Amyloidosis in a totAL of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archivAL tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were ALso anALyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focAL. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humorAL immunity to CT7, but sero reactivity was observed in individuAL patients to other CTAs. This study identifies CT7 as the prevALent CTA in plasma cells of patients with AL Amyloidosis. Further anALyses determining the biology of CTAs in AL Amyloidosis and their vALue as potentiAL targets for immunotherapy are warranted.
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Expression of D-type cyclins in AL Amyloidosis plasma cells
Journal of Clinical Pathology, 2012Co-Authors: John C. Lee, Carl O'hara, Tatiana Prokaeva, David C SeldinAbstract:Amyloid light chain (AL) Amyloidosis is a plasma cell (PC) disorder characterised by the overproduction of monoclonAL immunoglobulin light chains (LC). It can be treated effectively with chemotherapy with or without stem cell transplantation, proteasome inhibitors or immunomodulatory drugs. Diagnosing AL Amyloidosis requires the detection of tissue amyloid deposits in association with monoclonAL immunoglobulin LC production, which can be detected by serum or urine immunofixation electrophoresis (S/UIFE), serum free light chain (FLC) assay and/or bone marrow assessment of clonAL PCs.1 ,2 In some clinicAL circumstances, it may be necessary to prove the monoclonAL LC nature of the amyloid using immunoelectron microscopy or mass spectrometry.3 The current modALities to demonstrate the clonALity of amyloidogenic PCs in the bone marrow include flow cytometry, immunohistochemistry (IHC) and in situ hybridisation (ISH). Owing to the smALl volume of the PC population in AL Amyloidosis, however, detection of clonAL PCs is often difficult.4 ,5 Cyclin D dysregulation has been proposed to be a common mechanism in PC disorders, as in multiple myeloma; the majority of patients have dysregulated cyclin D expression.6 This has not been extensively investigated in AL Amyloidosis. In this study, we evALuated cyclin D1, D2 and D3 protein expression in AL Amyloidosis, and compared cyclin D positivity to other conventionAL laboratory parameters as a diagnostic tool and as a potentiAL biomarker for minimAL residuAL disease. ### Patient selection Thirty-four AL Amyloidosis patients diagnosed based on published guidelines7 ,8 who had a bone marrow biopsy between June and August 2008 were included in this study, with permission of the Boston University MedicAL Center InstitutionAL Review Board. Six patients were newly diagnosed, while 28 had received prior treatment including intravenous melphALan with autologous stem cell transplantation, orAL melphALan or lenALidomide or intravenous bortezomib. Ten patients with no evidence of …
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PreclinicAL Development of siRNA Therapeutics for AL Amyloidosis
Gene Therapy, 2011Co-Authors: Beth M. Hovey, Carl O'hara, Jennifer E. Ward, P Soo Hoo, Lawreen H. Connors, David C SeldinAbstract:Amyloid light chain (AL) Amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonAL immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed smALl interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL Amyloidosis, we have demonstrated that these siRNAs can significantly reduce locAL production and circulating levels of LC. This model system highlights the therapeutic potentiAL of siRNA for AL Amyloidosis.
Vaishali Sanchorawala - One of the best experts on this subject based on the ideXlab platform.
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Long-term outcome of kidney transplantation in AL Amyloidosis
Kidney International, 2019Co-Authors: Avital Angel-korman, Vaishali Sanchorawala, J. Mark Sloan, Gheorghe Doros, Lauren Stern, Shayna Sarosiek, Andrea HavasiAbstract:Therapies for AL Amyloidosis have dramaticALly improved, leading to longer patient survivAL; however, more AL Amyloidosis patients are reaching end-stage renAL disease (ESRD). There are no clear guidelines regarding eligibility for kidney transplantation in patients with AL Amyloidosis, and data on outcomes are limited. We evALuated the clinicAL and laboratory data of 49 patients who were followed in the Amyloidosis Center at Boston University and underwent kidney transplantation at a center in the United States between 1987-2017. During a median follow-up of 7.2 years (range 0-19), the median patient survivAL from diagnosis was 15.4 years, and from kidney transplantation was 10.5 years. One, three, and five-year graft survivAL were 94%, 89%, and 81%, respectively. Patients with hematologic complete response or very good partiAL response prior to kidney transplantation had significantly better patient survivAL than patients with partiAL response or no response, and the median time to graft loss was 10.4 years versus 5.5 years, respectively. This is the largest published series of kidney transplantation in patients with AL Amyloidosis, suggesting that kidney transplantation can have a good outcome in carefully selected patients, particularly in those who have achieved a complete response or very good partiAL response at the time of kidney transplantation.
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Bendamustine-Induced Nephrogenic Diabetes Insipidus in a Patient With AL Amyloidosis
American Journal of Kidney Diseases, 2017Co-Authors: Nsabimana A. Uwumugambi, Vaishali Sanchorawala, Lauren Stern, Anthony C Shelton, Craig E. GordonAbstract:Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principAL cells of the renAL collecting ducts to respond to antidiuretic hormone and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and severAL chemotherapeutic agents have been reported to cause it. Bendamustine is a traditionAL chemotherapeutic agent being studied for treatment for relapsed systemic AL Amyloidosis. We report a case of a 59-year-old man with AL Amyloidosis who developed partiAL nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL Amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, ALlowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy.
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ClinicAL presentation and treatment responses in IgM-related AL Amyloidosis
Amyloid, 2015Co-Authors: Moussa Sissoko, David C Seldin, John L. Berk, Vaishali Sanchorawala, Brian Sworder, Kenneth Angelino, Mike Broce, J. Mark SloanAbstract:Amyloid light-chain (AL) Amyloidosis is a multi-organ disease due to deposition of misfolded monoclonAL immunoglobulin light chains. IgM AL Amyloidosis is a rare variant, about 6% of AL Amyloidosis cases, and more data are needed for treatment guidance. In IgM AL Amyloidosis, the clonAL cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinicAL and laboratory features of 95 patients with IgM AL Amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% mALes. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinAL tract (17%). Treatment responses were anALyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. OverALl hematologic response rates and very good partiAL or complete hematologic response rates, respectively, were: high-dose melphALan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose ALkylating agents (MelphALan or cyclophosphamide) 63%;19%. OverALl, 5-year survivAL rates were significantly higher in patients with a hematologicAL response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typicALly expected in AL Amyloidosis.
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ClinicAL Presentation and Treatment Responses In IgM-Related AL Amyloidosis
Blood, 2013Co-Authors: Vaishali Sanchorawala, David C Seldin, John L. Berk, Brian Sworder, John Mark SloanAbstract:AL Amyloidosis is a multiorgan disease due to deposition of misfolded monoclonAL immunoglobulin light chains. AL Amyloidosis associated with IgM paraproteinemia is a rare variant of this disease, constituting approximately 6% of AL Amyloidosis cases in the literature. The clonAL cell of origin may be a plasma cell or a lymphoplasmacytic cell, and treatments targeting each of these populations have been employed. This study defines the clinicAL and laboratory characteristics of IgM-related AL Amyloidosis patients as well as their response to different therapeutic regimens. We identified 94 patients with IgM-related AL Amyloidosis evALuated at the BUMC Amyloidosis Center from 2003 through 2012 for which data was available on 50 who completed treatment. The median age at diagnosis was 65 years (range: 42-79 years) with 31 (62 %) mALes. The most commonly involved organ was the kidney (59%) followed by heart (37%) and GI tract (22%). The mean IgM was 1049 g/dL (range: 29-9130). The clonAL population had lambda light chain restriction in 34 (68%) of patients. Patients were categorized into 5 treatment groups: high-dose melphALan/stem cell transplant (HDM/SCT), bortezomib-based, non-transplant ALkylating agents based (melphALan or cyclophosphamide), immunomodulatory agents (IMiDs), and rituximab-based. This grouping was not mutuALly exclusive. The highest hematologic response rate was observed with HDM/SCT (10/10: 100%), followed by non-transplant ALkylating agents (16/22: 73%), bortezomib (7/10: 70%) rituximab (9/13: 69%) then by IMiDs (2/4: 50%). We did not observe an association between positive response to treatment and organ involvement, sex or age at diagnosis. In conclusion, IgM-related ALAmyloidosis is an unusuAL variant of AL Amyloidosis. Multiple active therapies with different mechanisms of action exist; treatment should be tailored based upon clinicopathologic and patient-specific factors. Disclosures: Sloan: Millenium: Consultancy.
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Macroglossia - not ALways AL Amyloidosis.
Amyloid, 2011Co-Authors: Andrew J. Cowan, David C Seldin, Martha Skinner, John L. Berk, John Mark Sloan, Carl O'hara, Vaishali SanchorawalaAbstract:AL Amyloidosis and transthyretin (ATTR) Amyloidosis are the most frequent forms of systemic Amyloidosis diagnosed in the United States. Macroglossia is considered to be a pathognomonic feature of AL Amyloidosis. We report on two cases of systemic Amyloidosis with macroglossia that defied routine clinicAL diagnosis, in which the deposits were typed as ATTR in one case and AL in the other using immunoelectron microscopy. These cases highlight: (1) the difficulty of typing Amyloidosis on clinicAL criteria ALone; (2) the utility of immunoelectron microscopy and (3) that macroglossia, while occurring much more frequently in AL, can ALso accompany ATTR Amyloidosis.
Giampaolo Merlini - One of the best experts on this subject based on the ideXlab platform.
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Improved outcomes for kidney transplantation in AL Amyloidosis: impact on practice.
Kidney International, 2019Co-Authors: Mario Nuvolone, Giampaolo MerliniAbstract:Effective therapies for Ig light chain (AL) Amyloidosis has led to an increasing proportion of patients with end-stage renAL disease requiring renAL replacement therapy, yet kidney transplantation is seldom performed in this setting due to concerns of renAL and extrarenAL disease progression. Angel-Korman et AL. report unprecedented positive long-term outcomes in the largest series of kidney transplantation in AL Amyloidosis providing the basis for a more proactive approach to this procedure.
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Management of the elderly patient with AL Amyloidosis.
European Journal of Internal Medicine, 2018Co-Authors: Mario Nuvolone, Paolo Milani, Giovanni Palladini, Giampaolo MerliniAbstract:Abstract Systemic immunoglobulin light chain (AL) Amyloidosis is an aging-associated protein misfolding and deposition disease. This condition is caused by a smALl and otherwise indolent plasma cell (or B cell) clone secreting an unstable circulating light chain, which misfolds and deposits as amyloid fibrils possibly leading to progressive dysfunction of affected organs. AL Amyloidosis can occur in the typicAL setting of other, rarer forms of systemic Amyloidosis and can mimic other more prevALent conditions of the elderly. Therefore, its diagnosis requires a high degree of clinicAL suspicion and reliable diagnostic tools for accurate amyloid typing, available at speciALized referrAL centers. In AL Amyloidosis, frailty is dictated by the type and severity of organ involvement, with heart involvement being the main determinant of morbidity and mortALity. Still, given a similar disease stage, elderly patients with AL Amyloidosis are often an even frailer group, due to significant comorbidities, associated disability and polypharmacotherapy, socioeconomic restrictions, and limited access to clinicAL triALs. Recent improvements in the use of biomarkers for early diagnosis, risk stratification and response monitoring, the flourishing of novel, effective anti-plasma cell therapies developed against multiple myeloma and adapted to treat AL Amyloidosis, and possibly the introduction of anti-amyloid therapies are rapidly changing the clinicAL management of this disease and are reflected by improved outcomes. Of note, hematologic and organ responses in elderly patients with AL Amyloidosis do translate in better outcome, advocating the importance of treating these patients and striving for a rapid response to therapy ALso in this chALlenging clinicAL setting.
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AL Amyloidosis from molecular mechanisms to targeted therapies
Hematology, 2017Co-Authors: Giampaolo MerliniAbstract:Systemic Amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vitAL organs. The most common systemic Amyloidosis, light-chain (AL) Amyloidosis, is caused by misfolded light chains produced by a smALl, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a chALlenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vitAL. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overALl survivAL, making AL Amyloidosis the most successful model of ALl amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL Amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
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MonoclonAL IgM-related AL Amyloidosis
Best Practice & Research Clinical Haematology, 2016Co-Authors: Paolo Milani, Giampaolo MerliniAbstract:MonoclonAL immunoglobulin M (IgM)-related light chain (AL) Amyloidosis, which accounts for 5%-7% of ALl AL Amyloidosis cases, is a distinct clinicAL entity that poses specific chALlenges to clinicians. SeverAL studies reported that ALthough there is a substantiAL overlap, the pattern of organ involvement is peculiar, with higher frequencies of lung, lymph nodes, and peripherAL nervous system involvement. A recent collaborative study from three European referrAL centers, defined that cardiac involvement, advanced Mayo disease stage, neuropathic, and liver involvement were independent factors that had impact on survivAL in IgM-AL Amyloidosis patients. Once the diagnosis of Amyloidosis is made, correct amyloid typing is necessary to design appropriate therapy and follow-up. Treatment is focused on the suppression of the clone, and fast reduction of the circulating free light chains. New drugs targeting the amyloid deposits will be used in combination with anti-clone therapies.
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Treatment of IgM-Associated AL Amyloidosis With the Combination of Rituximab, Bortezomib, and Dexamethasone
Clinical Lymphoma Myeloma and Leukemia, 2011Co-Authors: Giovanni Palladini, Paolo Milani, Andrea Foli, Paola Russo, Laura Obici, Francesca Lavatelli, Giampaolo MerliniAbstract:IgM-associated AL Amyloidosis is a rare clinicAL entity with distinctive clinicAL characteristics. Little is known on the applicability of treatment regimens designed for WALdenstrom's macroglobulinemia (WM) to IgM-AL Amyloidosis. Bortezomib is highly effective in AL Amyloidosis and the combination of rituximab, bortezomib, and dexamethasone (RBDex) has been successfully tested in WM. Starting in May 2009 we prospectively treated with RBDex 10 patients with IgM-AL Amyloidosis. Hematologic response was achieved in 78% of patients, including 3 refractory to previous rituximab. Severe adverse events (grade ≥ 3) were observed in 3 cases. Treatment of IgM-AL Amyloidosis with RBDex warrants further investigation in the setting of internationAL clinicAL triALs.
Carl O'hara - One of the best experts on this subject based on the ideXlab platform.
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Bone Marrow Biopsy and Its Utility in the Diagnosis of AL Amyloidosis
Current Clinical Pathology, 2015Co-Authors: John C. Lee, Lawreen H. Connors, Carl O'haraAbstract:A bone marrow biopsy is essentiAL for the initiAL diagnosis of AL Amyloidosis. A bone marrow biopsy is ALso important in establishing a baseline for treatment and is one of the factors in predicting prognosis. The bone marrow biopsy can be used in assessing for the presence of amyloid, estimating the plasma cell volume, and determining whether a clonAL amyloidogenic plasma cell population is present or not. In tandem with other studies, bone marrow biopsies can ALso be used to monitor treatment and assess for complete response, partiAL response, or no response to the various therapies being used in AL Amyloidosis. A bone marrow aspirate can supplement the biopsy for use in flow cytometry in determining the presence of a clonAL plasma cell population and for use in cytogenetics. With the precedent being set with multiple myeloma, greater understanding of cytogenetic abnormALities is being discovered in AL Amyloidosis and may play a role in prognosis and treatment. The following chapter will discuss the workup that we employ in bone marrow biopsies from suspected or confirmed AL Amyloidosis patients and some of the new discoveries being made in AL Amyloidosis using bone marrow specimens.
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Expression of D-type cyclins in AL Amyloidosis plasma cells
Journal of Clinical Pathology, 2012Co-Authors: John C. Lee, Carl O'hara, Tatiana Prokaeva, David C SeldinAbstract:Amyloid light chain (AL) Amyloidosis is a plasma cell (PC) disorder characterised by the overproduction of monoclonAL immunoglobulin light chains (LC). It can be treated effectively with chemotherapy with or without stem cell transplantation, proteasome inhibitors or immunomodulatory drugs. Diagnosing AL Amyloidosis requires the detection of tissue amyloid deposits in association with monoclonAL immunoglobulin LC production, which can be detected by serum or urine immunofixation electrophoresis (S/UIFE), serum free light chain (FLC) assay and/or bone marrow assessment of clonAL PCs.1 ,2 In some clinicAL circumstances, it may be necessary to prove the monoclonAL LC nature of the amyloid using immunoelectron microscopy or mass spectrometry.3 The current modALities to demonstrate the clonALity of amyloidogenic PCs in the bone marrow include flow cytometry, immunohistochemistry (IHC) and in situ hybridisation (ISH). Owing to the smALl volume of the PC population in AL Amyloidosis, however, detection of clonAL PCs is often difficult.4 ,5 Cyclin D dysregulation has been proposed to be a common mechanism in PC disorders, as in multiple myeloma; the majority of patients have dysregulated cyclin D expression.6 This has not been extensively investigated in AL Amyloidosis. In this study, we evALuated cyclin D1, D2 and D3 protein expression in AL Amyloidosis, and compared cyclin D positivity to other conventionAL laboratory parameters as a diagnostic tool and as a potentiAL biomarker for minimAL residuAL disease. ### Patient selection Thirty-four AL Amyloidosis patients diagnosed based on published guidelines7 ,8 who had a bone marrow biopsy between June and August 2008 were included in this study, with permission of the Boston University MedicAL Center InstitutionAL Review Board. Six patients were newly diagnosed, while 28 had received prior treatment including intravenous melphALan with autologous stem cell transplantation, orAL melphALan or lenALidomide or intravenous bortezomib. Ten patients with no evidence of …
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PreclinicAL Development of siRNA Therapeutics for AL Amyloidosis
Gene Therapy, 2011Co-Authors: Beth M. Hovey, Carl O'hara, Jennifer E. Ward, P Soo Hoo, Lawreen H. Connors, David C SeldinAbstract:Amyloid light chain (AL) Amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonAL immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed smALl interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL Amyloidosis, we have demonstrated that these siRNAs can significantly reduce locAL production and circulating levels of LC. This model system highlights the therapeutic potentiAL of siRNA for AL Amyloidosis.
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Macroglossia - not ALways AL Amyloidosis.
Amyloid, 2011Co-Authors: Andrew J. Cowan, David C Seldin, Martha Skinner, John L. Berk, John Mark Sloan, Carl O'hara, Vaishali SanchorawalaAbstract:AL Amyloidosis and transthyretin (ATTR) Amyloidosis are the most frequent forms of systemic Amyloidosis diagnosed in the United States. Macroglossia is considered to be a pathognomonic feature of AL Amyloidosis. We report on two cases of systemic Amyloidosis with macroglossia that defied routine clinicAL diagnosis, in which the deposits were typed as ATTR in one case and AL in the other using immunoelectron microscopy. These cases highlight: (1) the difficulty of typing Amyloidosis on clinicAL criteria ALone; (2) the utility of immunoelectron microscopy and (3) that macroglossia, while occurring much more frequently in AL, can ALso accompany ATTR Amyloidosis.
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Dysregulation of miRNAs In AL Amyloidosis
Blood, 2010Co-Authors: Liangping Weng, Carl O'hara, Lawreen H. Connors, Brain Spencer, Pam Soo Hoo, David C SeldinAbstract:Abstract 4648 Bone marrow plasma cells (BMPC) were purified from aspirates obtained from patients with AL Amyloidosis using anti-CD138 immunomagnetic beads, and from controls. Expression levels of micro RNAs (miRNAs) were compared by microarray. The levels of ten miRNAs were found to be increased more than 1.5-fold in BMPC of AL Amyloidosis patients. These results were confirmed using stem-loop RT-qPCR for miR-148a, miR-26a, and miR-16, the most highly upregulated miRNAs in the AL samples. miR-16, a micro RNA linked to other hematopoietic diseases, was significantly increased in the AL group at baseline and ALso in treated patients with persistent monoclonAL plasma cells in the bone marrow, but not in patients who achieved a hematologic remission after therapy and normAL polyclonAL BMPCs. miR-16 can be derived from the miR-16-1/mirR-15a cluster on chromosome 13 or the miR-16-2/miR-15b cluster on chromosome 3. The expression of miR-15b was much higher than miR15a in AL and control BMPC samples; this suggests that miR-16 in plasma cells is mostly derived from chromosome 3. The anti-apoptosis gene BCL-2, a putative target mRNA that can be down-regulated by miR-16, was present in the BMPCs from the AL group despite the elevated levels of miR-16. Our data suggest that miRNAs are dysregulated in clonAL plasma cells from AL Amyloidosis patients and that abnormAL levels of miRNAs may be potentiAL biomarkers for disease. Disclosures: No relevant conflicts of interest to declare.
David Lavergne - One of the best experts on this subject based on the ideXlab platform.
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Diagnostic score of cardiac involvement in AL Amyloidosis.
European Heart Journal - Cardiovascular Imaging, 2019Co-Authors: Martin Nicol, David Lavergne, Arnaud Jaccard, Mathilde Baudet, S. Brun, Stephanie Harel, Bruno Royer, Marguerite Vignon, Olivier Lairez, David AttiasAbstract:AIMS Early diagnosis of cardiac involvement is a key issue in the management of AL Amyloidosis. Our objective was to establish a diagnostic score of cardiac involvement in AL Amyloidosis and to compare it with the current consensus criteria [i.e. left ventricular hypertrophy >12 mm and N-terminAL pro b-type natriuretic peptide (NT-proBNP) >332 ng/L]. METHODS AND RESULTS We carried out a prospective and multicenter study on AL Amyloidosis patients who underwent cardiac evALuation including clinicAL examination, electrocardiography (ECG), cardiac biomarkers, transthoracic echocardiography (TTE), and cardiac magnetic resonance imaging (CMR). Cardiac involvement was based on CMR and/or endomyocardiAL biopsy. In a derivation cohort of 114 patients (82 with cardiac involvement), the highest diagnostic accuracy was observed with NT-proBNP and troponin blood levels, TTE-derived globAL longitudinAL strain (LS), and apicAL to basAL LS gradient. By using multivariate anALysis, we established a diagnostic score including globAL LS ≥-17% (1 point), apicAL/(basAL + median) LS ≥0.90 (1 point), and troponin T >35 ng/L (1 point). A score >1 was associated with sensitivity of 94% and specificity of 97%, an area under the curve of 0.98 [95% confidence intervAL (CI) 0.93-0.99] as well as a net reclassification index of 0.39 (95% CI 0.28-0.46) when compared with consensus criteria. In a vALidation cohort of 73 AL Amyloidosis patients, the area under the receiver operating characteristic curve of the diagnostic score was 0.97 (95% CI 0.90-0.99). CONCLUSION Combining T troponin blood levels and two echo-derived strain parameters leads to very high accuracy for diagnosing cardiac involvement in AL amyloid patients.
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AL Amyloidosis.
Orphanet Journal of Rare Diseases, 2012Co-Authors: Estelle Desport, Franck Bridoux, Christophe Sirac, Sébastien Delbes, Sébastien Bender, Béatrice Fernandez, Nathalie Quellard, Corinne Lacombe, Jean-michel Goujon, David LavergneAbstract:UNLABELLED: DEFINITION OF THE DISEASE: AL Amyloidosis results from extra-cellular deposition of fibril-forming monoclonAL immunoglobulin (Ig) light chains (LC) (most commonly of lambda isotype) usuALly secreted by a smALl plasma cell clone. Most patients have evidence of isolated monoclonAL gammopathy or smoldering myeloma, and the occurrence of AL Amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusuAL. The key event in the development of AL Amyloidosis is the change in the secondary or tertiary structure of an abnormAL monoclonAL LC, which results in instable conformation. This conformationAL change is responsible for abnormAL folding of the LC, rich in β leaves, which assemble into monomers that stack together to form amyloid fibrils. EPIDEMIOLOGY: AL Amyloidosis is the most common type of systemic amyloidois in developed countries with an estimated incidence of 9 cases/million inhabitant/year. The average age of diagnosed patients is 65 years and less than 10% of patients are under 50. CLINICAL DESCRIPTION: The clinicAL presentation is protean, because of the wide number of tissues or organs that may be affected. The most common presenting symptoms are asthenia and dyspnoea, which are poorly specific and may account for delayed diagnosis. RenAL manifestations are the most frequent, affecting two thirds of patients at presentation. They are characterized by heavy proteinuria, with nephrotic syndrome and impaired renAL function in hALf of the patients. Heart involvement, which is present at diagnosis in more than 50% of patients, leading to restrictive cardiopathy, is the most serious complication and engages prognosis. DIAGNOSTIC METHODS: The diagnosis relies on pathologicAL examination of an involved site showing Congo red-positive amyloid deposits, with typicAL apple-green birefringence under polarized light, that stain positive with an anti-LC antibody by immunohistochemistry and/or immunofluorescence. Due to the systemic nature of the disease, non-invasive biopsies such as abdominAL fat aspiration should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications. DIFFERENTIAL DIAGNOSIS: Systemic AL Amyloidosis should be distinguished from other diseases related to deposition of monoclonAL LC, and from other forms of systemic Amyloidosis. When pathologicAL studies have failed to identify the nature of amyloid deposits, genetic studies should be performed to diagnose hereditary Amyloidosis. MANAGEMENT: Treatment of AL Amyloidosis is based on chemotherapy, aimed at controlling the underlying plasma clone that produces amyloidogenic LC. The hematologicAL response should be carefully checked by seriAL measurements of serum free LC. The association of an ALkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients and is considered as the current reference treatment. New agents used in the treatment of multiple myeloma are under investigation and appear to increase hematologicAL response rates. Symptomatic measures and supportive care is necessary in patients with organ failure. Noticeably, usuAL treatments for cardiac failure (i.e. cALcium inhibitors, β-blockers, angiotensin converting enzyme inhibitors) are inefficient or even dangerous in patients with amyloid heart disease, that should be managed using diuretics. Amiodarone and pace maker implantation should be considered in patients with rhythm or conduction abnormALities. In selected cases, heart and kidney transplantation may be associated with prolonged patient and graft survivAL. PROGNOSIS: SurvivAL in AL Amyloidosis depends on the spectrum of organ involvement (amyloid heart disease being the main prognosis factor), the severity of individuAL organs involved and haematologicAL response to treatment.
