Prevalencia de estenosis aórtica moderada-grave en pacientes con amiloidosis cardiaca en un centro de referencia / Prevalence of moderate-severe aortic stenosis in patients with cardiac amyloidosis in a referral center

Resumen Antecedentes: La estenosis aórtica (EA) es actualmente la enfermedad valvular más frecuente, con una prevalencia estimada de más del 4 % en octogenarios. Objetivo: Describir la prevalencia de estenosis aórtica (EA) moderada-grave en pacientes con amiloidosis por transtiretina wild type (ATTRwt). Además, describir las características clínicas, ecocardiográficas y la evolución en este grupo de pacientes. Método: Estudio de cohorte retrospectiva de pacientes con diagnóstico de ATTRwt, pertenecientes al Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, en el periodo del 30/11/2007 al 31/05/2021. El seguimiento de los pacientes se realizó a través de la historia clínica electrónica de la institución. Se estimó la prevalencia de EA moderada-grave, que se presenta como porcentaje con su intervalo de confianza del 95% (IC 95%). Se compararon las características por grupos según tuvieran o no EA moderada-grave. Resultados: Se incluyeron 104 pacientes con diagnóstico de ATTRwt. La mediana de seguimiento fue de 476 días [rango intercuartílico: 192-749]. La prevalencia de EA moderada-grave al momento del diagnóstico de ATTRwt fue del 10.5% (n = 11; IC95%: 5-18%). La mediana de edad de los pacientes con EA fue de 86 años [78-91] y predominó el sexo masculino (81.8%). La mayoría de los pacientes tenían el antecedente de insuficiencia cardiaca (n = 8) y fibrilación auricular (n = 8). Predominaron los pacientes con EA grave de bajo flujo y bajo gradiente (n = 7). Cuatro pacientes fueron sometidos a alguna intervención en la válvula aórtica. Durante el seguimiento, 5 pacientes (46%) tuvieron internaciones por insuficiencia cardiaca descompensada y 4 (36%) fallecieron. Conclusiones: En nuestra cohorte, la coexistencia de ambas patologías tuvo una prevalencia similar a la reportada en la literatura internacional. Se trató de una población añosa con alto porcentaje de fibrilación auricular y antecedente de insuficiencia cardiaca. La mayoría presentaron EA grave de bajo flujo y bajo gradiente.

Abstract Background: Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians. Objective: To describe the prevalence of moderate-severe aortic stenosis (AS) in patients with wild type transthyretin amyloidosis (ATTRwt). Also, describe the clinical features, echocardiographic characteristics and clinical evolution. Method: Retrospective cohort of patients with diagnosis of ATTRwt, belonging to Hospital Italiano de Buenos Aires Institutional Amyloidosis Registry, from 30/11/2007 to 31/05/2021. Patients follow up was carried out through the institution clinical history. The prevalence of moderate-severe AE was estimated and presented as a percentage with its 95% confidence interval (95% CI). The characteristics were compared by groups according to whether or not they had moderate-severe AS. Results: 104 patients with ATTRwt were included. Median follow up was 476 days [interquartile range: 192-749]. Moderate-severe AS prevalence at the ATTRwt time of diagnosis was 10.5% (n = 11; 95% CI: 5-18%). The median age of patients with AS moderate-severe at the time of diagnosis of ATTRwt was 86 years [78-91] and the male sex predominated (82%). Most of the patients had a history of heart failure (n = 8) and atrial fibrillation (n = 8) prior to the diagnosis of ATTRwt. Most of the patients were subclassified as low flow low gradient severe AS group (n = 7). Four patients underwent some intervention on the aortic valve. During follow-up, 5 patients (46%) were hospitalized for decompensated heart failure and 4 (36%) died. Conclusions: In our cohort, the coexistence of both pathologies had a similar prevalence as reported in the international literature. It was an elderly population with a high percentage of atrial fibrillation and history of heart failure. Most of the patients presented with severe AS with low flow low gradient.

Review and Progress in the Treatment of Renal Light Chain Amyloidosis / 罕见病研究

Renal light chain amyloidosis (AL amyloidosis) had poor prognosis before the 21st century. However, the treatment of AL amyloidosis has made great progress in the last decade. We reviewed traditional treatments of AL amyloidosis such as alkylating agents, proteasome inhibitors, and recent advances such as monoclonal antibodies. Bortezomib improved the hematological response and survival effectively of the patients, and the combination of Daratumumab brings faster and deeper hematological response, increasing the response rate of target organs such as the kidneys and heart. The renal response was significant higher in the patients with the therapy of Daratumumab, part of them could achieve very good partial response or better renal response. Autologous hematopoietic stem cell transplantation(auto-HSCT)improves hematological as well as organ response, and could be the first choice among eligible patients. Kidney transplantation is a feasible option for those with good hematological response.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro / Experiência de vida-real com inotersena no CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro

Abstract Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. Objective To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Methods Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Results Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. Conclusion The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Resumo Antecedentes Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. Objetivo Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). Métodos Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1-primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. Resultados Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. Conclusão O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Heart Failure Management of Patients with Amyloid Cardiomyopathy

Abstract Cardiac amyloidosis (CA) can lead to progressive heart failure (HF) by depositing insoluble amyloid fibrils within the myocardial extracellular space, resulting in an infiltrative and restrictive cardiomyopathy. Although CA was previously perceived as rare and incurable, recent advances in diagnostics and emerging therapies have been changing this outlook. It is crucial to spread awareness about CA to facilitate earlier diagnosis and proper therapeutic interventions, enhancing patient prognosis and survival. Currently, there is an estimated delay of 2 years from symptom onset to diagnosis, typically involving consultation with an average of 5 different professionals. Advances in cardiovascular imaging have facilitated earlier and more accurate diagnosis, reducing the necessity for invasive procedures, such as endomyocardial biopsy. Presently, tafamidis is the only drug that has been shown to offer prognostic benefits in ATTR-CA. Tafamidis is a highly specific medication targeting the circulating TTR protein, stabilizing the TTR tetramer to prevent its dissociation into amyloidogenic monomers that deposit in the myocardium. Alongside specific amyloidosis therapy, supportive HF treatment may be required; however, managing CA with medications typically used for HF with reduced ejection fraction (HFrEF) can be challenging due to potential intolerance. The effectiveness of guideline-directed medical therapy (GDMT) remains undetermined and still requires evaluation through randomized controlled clinical trials (RCCTs). Thus, the treatment cornerstone remains the judicious use of loop diuretics and mineralocorticoid receptor antagonists to control volume overload. Due to the safety profile, not adversely affecting hemodynamics or renal function, sodium-glucose transport protein 2 (SGLT2) inhibitors may be an effective treatment for CA, but they also still require evaluation through RCCTs.

¿Qué hay de nuevo en el diagnóstico de amiloidosis? / What is new in diagnosis of amyloidosis?

La amiloidosis siempre ha representado un desafío diagnóstico. En el año 2020, el Grupo de Estudio de Amiloidosis (GEA), confeccionó la Guía de Práctica Clínica para el Diagnóstico de Amiloidosis. Nuevas líneas de investigación se han desarrollado posteriormente. Esta revisión narrativa tiene como intención explorar el estado del arte en el diagnóstico de la amiloidosis. En pacientes con amiloidosis se recomienda la tipificación de la proteína mediante espectrometría de masa, técnica de difícil ejecución por requerir de microdisectores láser para la preparación de la muestra. Algunas publicaciones recientes proponen otros métodos para obtener la muestra de amiloide que se va a analizar, permitiendo prescindir de la microdisección. Por otra parte, en pacientes con Amiloidosis ATTR confirmada, la recomendación de secuenciar el gen amiloidogénico se encontraba destinada a los casos sospechosos de ATTR hereditaria (ATTRv,), pero actualmente esta se ha extendido a todos los pacientes sin importar la edad. En lo que respecta a los estudios complementarios orientados al diagnóstico de compromiso cardíaco, se ha propuesto el uso de la inteligencia artificial para su interpretación, permitiendo la detección temprana de la enfermedad y el correcto diagnóstico diferencial. Para el diagnóstico de neuropatía, las últimas publicaciones proponen el uso de la cadena ligera de neurofilamento sérica, que también podría resultar un indicador útil para seguimiento. Finalmente, con referencia a la amiloidosis AL, la comunidad científica se encuentra interesada en definir qué características determinan el carácter amiloidogénico de las cadenas livianas. La N-glicosilación de dichas proteínas impresiona ser uno de los determinantes en cuestión. (AU)

Amyloidosis has always represented a diagnostic challenge. In 2020, the Amyloidosis Study Group (ASG) developed the "Clinical Practice Guideline for the Diagnosis of Amyloidosis". New lines of research have subsequently emerged. This narrative review aims to explore the state of the art in the diagnosis of amyloidosis diagnosis. In patients with amyloidosis, protein typing by mass spectrometry is recommended, a technique hard to perform because it requires laser microdissection for sample preparation. Recent publications propose other methods to obtain the amyloid sample to be analyzed, making it possible to dispense with microdissection. On the other hand, in patients with confirmed TTR amyloidosis (aTTR), the recommendation to sequence the amyloidogenic gene was intended for suspected cases of hereditary aTTR but has now been extended to all patients regardless of age. (AU)

¿Qué hay de nuevo en el tratamiento de amiloidosis por cadenas livianas? Parte 1: cadenas livianas / What is new in light chain amyloidosis treatment? Part 1: lightweight chains

La amiloidosis AL es una enfermedad debida al depósito, en órganos y tejidos, de fibrillas formadas por cadenas livianas producidas de forma patológica por plasmocitos clonales. Su tratamiento actualmente está orientado a erradicar el clon de células plasmáticas; este históricamente se extrapoló de tratamientos disponibles y estudiados para otras discrasias sanguíneas. En el año 2020, el Grupo de Estudio de Amiloidosis (GEA) confeccionó distintas guías de práctica clínica para el tratamiento de la amiloidosis AL. Desde entonces se han publicado ensayos clínicos que arrojan contundencia al conocimiento disponible hasta el momento, y están en desarrollo nuevas líneas de investigación que robustecen y estimulan el estudio en el área. En esta revisión se realiza una actualización de las guías existentes en lo que respecta al tratamiento de la amiloidosis por cadenas livianas.Como evidencia de relevancia, en el último año estuvieron disponibles resultados de ensayos clínicos que respaldan el uso de esquemas basados en daratumumab (un anticuerpo monoclonal anti-CD38+) para pacientes con diagnóstico reciente de amiloidosis AL como primera línea. Además, para el tratamiento de la amiloidosis AL refractaria o recaída, la disponibilidad de bibliografía respaldatoria es escasa y extrapolada del tratamiento del mieloma múltiple; sin embargo, actualmente existe evidencia de calidad para recomendar el uso de ixazomib, un inhibidor de proteosoma reversible por vía oral disponible en la Argentina desde 2020. Por último, se mencionan algunas líneas de investigación con otros anticuerpos monoclonales y terapéuticas basadas en el uso de CAR-T cells. (AU)

AL amyloidosis is a disease caused by the deposit in different organs and tissues of protein fibrils formed by light chains synthetized by pathological clonal plasma cells. Its treatment is currently aimed at eradicating this plasma cell clone and it has been historically extrapolated from available and validated treatments for other blood dyscrasias. In 2020, the Amyloidosis Study Group prepared different clinical practice guidelines for the treatment of AL amyloidosis.Since then, clinical trials have been published that confirm and strengthen the knowledge available up to now, and new lines of research are being developed that stimulate study in the area. In this review, an update of the existing guidelines regarding the treatment of AL amyloidosis is made. As relevant evidence, in the last year, results of clinical trials have been made available that support the use of regimens based on Daratumumab (an anti-CD38+ monoclonal antibody) for patients with newly diagnosed AL amyloidosis as first line therapy. In addition, for the treatment of refractory or relapsed AL amyloidosis, where the availability of supporting literature is scant and extrapolated from the treatment of multiple myeloma, there is currently quality evidence to recommend the use of ixazomib, an oral reversible proteasome inhibitor, only available in Argentina since 2020. Finally, some research lines exploring the efficacy of other monoclonal antibodies and therapeutic experiments based on the use of CAR-T cells are mentioned. (AU)

Insuficiencia cardiaca secundaria a amiloidosis AL: diagnóstico y tratamiento / Heart failure secondary to amyloidosis AL: diagnosis and treatment

Resumen La amiloidosis por depósito de cadenas livianas de inmunoglobulinas (AL) es una enfermedad poco frecuen te y subdiagnosticada. El mejor tratamiento disponible al momento es el trasplante autólogo de médula ósea (TMO). El compromiso cardíaco es el principal determi nante pronóstico en esta patología y en ocasiones un impedimento para recibir el TMO. Se presenta el caso de un varón de 44 años que consultó por signos y síntomas de insuficiencia cardiaca (IC) con biomarcadores cardia cos elevados. Se realizó un ecocardiograma transtorácico donde se objetivó aumento de espesores parietales con hipoquinesia global y fracción de eyección deteriorada en grado leve (50%). El paciente se internó en unidad coronaria para balance negativo y para estudio etiológico del cuadro. Ante la sospecha de enfermedad infiltrativa, se solicitaron un centellograma óseo con pirofosfato y cadenas livianas libres en suero. El centellograma óseo resultó no sugestivo para amiloidosis por transtiretina y las cadenas livianas libres mostraron una relación me nor a 0.26 con predominio lambda. Se realizó una biopsia de encía que confirmó el diagnóstico de amiloidosis AL. Posterior al diagnóstico comenzó tratamiento qui mioterápico específico con Ciclofosfamida, Bortezomib y Dexametasona (esquema CYBORD) y Daratumumab. Evolucionó con IC refractaria por lo que ingresó a lista de trasplante cardiaco, recibiendo el mismo al poco tiempo con buena evolución. Esto permitió reiniciar el esquema quimioterápico y en segundo término finalmente recibir el TMO, con buena evolución.

Abstract Light chain amyloidosis (AL) is a rare and underdi agnosed disease. The best treatment available is au tologous bone marrow transplantation (BMT). Cardiac involvement is the main prognostic determinant in this pathology and sometimes an impediment to re ceive BMT. We present a clinical case of a 44-year-old who consulted for signs and symptoms of heart failure (HF) with elevated cardiac biomarkers. A transthoracic echocardiogram showed increased wall thickness with global hypokinesia and mildly impaired ejection fraction (50%). The patient was admitted to the coronary unit for treatment with diuretics and for etiological study of the condition. In view of the suspicion of infiltrative disease, a bone scintigraphy with pyrophosphate and free light chains in serum were requested. The bone scintigraphy was not suggestive of transthyretin amyloidosis and the free light chains showed a ratio of less than 0.26 with lambda predominance. A gum biopsy was per formed and confirmed the diagnosis of AL amyloidosis. After diagnosis, specific chemotherapy treatment with Cyclophosphamide, Bortezomib and Dexamethasone (CYBORD scheme) and Daratumumab was started. He evolved with refractory HF so it was decided to admit him to the cardiac transplantation list, receiving the same soon after, with good evolution. This allowed the patient to restart the chemotherapy regimen and finally receive BMT, with good evolution.

Trasplante cardíaco y autólogo de células progenitoras hematopoyéticas en pacientes con amiloidosis AL / Cardiac and autologous stem cell transplantation hematopoietic in patients with AL amyloidosis

Resumen Objetivo: Describir la evolución de las cadenas livianas libres séricas (CLL) en el período comprendido entre el trasplante cardíaco ortotópico (TCO) y el trasplante de células progenitoras hematopoyéticas (TCPH), la respuesta hematológica al año tras el TCPH y el tratamiento quimioterápico e inmunosupresor en pacientes con amiloidosis AL. Método: Serie de casos de pacientes consecutivos con diagnóstico de amiloidosis AL que recibieron TCO seguido de TCPH del Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, entre enero de 2010 y noviembre de 2021. Se reportaron los valores de CLL entre trasplantes y al año del TCPH. Las variables cuantitativas se describieron como mediana e intervalo intercuartil, y las variables categóricas como frecuencias absolutas y relativas. Resultados: De 106 pacientes con amiloidosis AL, seis tuvieron TCO seguido de TCPH. La mediana de edad fue de 55 años. La mayoría eran hombres (n = 5). En el período entre trasplantes, la CLL involucrada disminuyó en dos pacientes y se mantuvo estable en tres. Todos lograron la remisión hematológica completa al año del TCPH. Un solo paciente presentó recaída en el órgano sólido trasplantado. Tacrolimus, micofenolato de mofetilo y corticoides fue el esquema inmunosupresor utilizado después del TCO. Conclusiones: El TCO representa una opción de tratamiento en pacientes con falla cardíaca grave por amiloidosis, permitiendo luego un tratamiento intensivo con quimioterapia de inducción y TCPH. Si bien faltan estudios, la terapia inmunosupresora después del TCO podría tener algún efecto sobre las células plasmáticas clonales.

Abstract Objective: To describe the evolution of serum free light chains (FLC) in the period between orthotopic heart transplantation (OHT) and autologous stem cell transplantation (ASCT), the hematological response one year after ASCT and chemotherapy and immunosuppressive treatment in patients with AL amyloidosis. Method: Case series of consecutive patients diagnosed with AL amyloidosis who received OHT followed by ASCT from the Institutional Registry of Amyloidosis of the Italian Hospital of Buenos Aires, between January 2010 and November 2021. FLC values between transplants and at year post ASCT. Quantitative variables were described with their median and interquartile range. Categorical variables as absolute and relative frequencies. Results: Of 106 patients with AL amyloidosis, 6 had an OHT followed by ASCT. The median age was 55 years. Most were men (n = 5). In the period between transplants, the involved CLL decreased in two patients and remained stable in three. All achieved complete hematologic remission 1 year after ASCT. A single patient presented relapse in the transplanted solid organ. Tacrolimus, mycophenolate mofetil, and corticosteroids were the immunosuppressive regimen used after OHT. Conclusions: OHT represents a treatment option in patients with severe heart failure due to amyloidosis, allowing later intensive treatment with induction chemotherapy and ASCT. Although studies are lacking, immunosuppressive therapy after OHT might have some effect on clonal plasma cells.

Hemorragia digestiva como forma de presentación poco usual de amiloidosis intestinal primaria: reporte de caso

La amiloidosis intestinal es una enfermedad sistémica rara y subdiagnosticada, la cual se caracteriza por el depósito extracelular de proteínas que se agrupan en fibras amiloides. Esta entidad es infrecuente y suele ser una forma de presentación en el contexto de una amiloidosis sistémica, cuyo diagnóstico se basa en la presencia a amiloide en la histología. La clínica suele ser inespecífica; diarrea crónica, pérdida de peso, dolor y distensión abdominal; siendo la hemorragia digestiva una manifestación muy poco frecuente. Se presenta el caso de una mujer de 61 años con clínica de baja de peso, distención abdominal, náuseas, vómitos y melena. En la tomografía se evidenció un engrosamiento mural de asas yeyunales con captación de contraste, hallazgo que se corroboró con enteroscopia anterógrada a doble balón en el cual se evidenciaron múltiples úlceras en yeyuno, signos de atrofia, friabilidad y dilatación de luz yeyunal. En la anatomía patológica se aprecia arquitectura vellositaria distorsionada y ulcerada con histoquímica positiva a Rojo Congo e inmunohistoquímica lambda (+++). Además, se realizó aspirado de médula ósea y biopsia de hueso compatible con infiltración de mieloma múltiple monoclonal a cadena Lambda. Durante la estancia hospitalaria la paciente cursó con complicaciones como la desnutrición crónica, infección recurrente y varios episodios de suboclusión intestinal; caracterizada por neumatosis intestinal; debido a múltiples episodios de estas complicaciones la paciente fallece. Dentro de la práctica clínica en gastroenterología la amiloidosis intestinal como parte del diagnóstico diferencial de la hemorragia digestiva alta es infrecuente, por lo que los antecedentes de diagnóstico de mieloma múltiple u otras gammapatías monoclonales asociadas a cadenas ligeras es crucial para un diagnóstico precoz y tratamiento adecuado.

Intestinal amyloidosis is a rare and underdiagnosed systemic disease, which is characterized by the extracellular deposition of proteins that are grouped into amyloid fibers. This entity is rare and is usually a form of presentation in the context of systemic amyloidosis, the diagnosis of which is based on the presence of amyloid in histology. The clinic is usually non-specific; chronic diarrhea, weight loss, abdominal pain and bloating; Gastrointestinal bleeding is a very rare manifestation. The case of a 61-year-old woman with symptoms of weight loss, abdominal distension, nausea, vomiting and long hair is presented. Tomographically, a wall thickening of jejunal loops with contrast uptake was evidenced, a finding that was corroborated by a double-balloon anterograde stereoscopy in which multiple were evidenced. The pathology shows distorted and ulcerated villous architecture with positive histochemistry for Congo Red and LAMBDA (+++) immunohistochemistry. In addition, bone marrow aspirate and bone biopsy compatible with infiltration of Lambda chain monoclonal multiple myeloma were performed. During the hospital stay, the patient developed complications such as chronic malnutrition, recurrent infection and several episodes of intestinal subocclusion; characterized by intestinal pneumatosis; due to multiple episodes of these complications, the patient died. Within clinical practice in gastroenterology, intestinal amyloidosis as part of the differential diagnosis of upper gastrointestinal bleeding is infrequent, so a history of diagnosis of multiple myeloma or other monoclonal gammopathy associated with light chains is crucial for early diagnosis and adequate treatment.

Secondary amyloidosis with concomitant gastric GIST and gastric adenocarcinoma - A case report

Secondary amyloidosis is a well-established entity and has been described in association with chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, bronchiectasis, tuberculosis, etc., It has also been reported in association with neoplasms such as Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, renal cell carcinoma, lung carcinoma, etc. However, only a few case reports documenting the association of amyloidosis with gastrointestinal tumor (GIST) and gastric adenocarcinoma are available in the literature. Hereby, we report a case of a 74-year-old male who presented with colicky abdominal pain and vomiting. Ultrasonography revealed a common bile duct (CBD) stone and a small extra-luminal gastric mass. Endoscopic retrograde cholangiopancreatography (ERCP) was performed to remove the CBD stone which revealed an incidental finding of gastric ulcer. A biopsy was taken from the gastric ulcer which on histopathological examination was confirmed as adenocarcinoma leading onto total gastrectomy. During total gastrectomy, an inadvertent injury to the spleen led to simultaneous splenectomy. Multiple samples from the gastric ulcer, the extra-luminal gastric mass, and the spleen were subjected to histopathological examination. Gastric ulcer was confirmed as adenocarcinoma, gastric extra-luminal mass was confirmed as GIST, and splenic examination revealed widespread deposition of amyloid which on Congo-red stain imparted an apple-green birefringence on polarizing microscopy. To the best of our knowledge, this is the first-ever case of such an association where gastric adenocarcinoma occurred with concomitant gastric GIST and secondary amyloidosis of the spleen.

Clinical characterization and outcomes of a cohort of colombian patients with AL Amyloidosis

Background: Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. Objective: This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. Methods: A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. Results: The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). Conclusions: In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.

Antecedentes: La amiloidosis por amiloide de cadenas ligeras (AL) se caracteriza por el depósito de fibrillas amiloides derivadas de cadenas ligeras de inmunoglobulinas monoclonales, lo que resulta en disfunción multiorgánica. Existen datos limitados sobre las características clínicas de la amiloidosis AL. Objetivo: Este estudio tiene como objetivo describir las características clínicas, tratamientos y desenlaces en pacientes colombianos con amiloidosis AL. Métodos: Se llevó a cabo un estudio descriptivo retrospectivo en tres centros de alta complejidad en Medellín, Colombia. Se incluyeron adultos con diagnóstico de amiloidosis AL entre 2012 y 2022. Se analizaron datos clínicos, de laboratorio, histológicos, de tratamiento y de supervivencia. Resultados: El estudio incluyó 63 pacientes. La afectación renal fue más prevalente (66%), seguida de la afectación cardíaca (61%). El 61% de los pacientes presentaron afectación multiorgánica. El depósito amiloide se detectó con mayor frecuencia en la biopsia renal (40%). El tratamiento basado en bortezomib se utilizó en el 68%, y el 23.8% recibió altas dosis de quimioterapia con trasplante autólogo de progenitores hematopoyéticos (ADQT-TAPH). Se observó respuesta hematológica en el 95% de los pacientes con datos disponibles. La respuesta de órgano cardíaca y renal fue del 15% y 14%, respectivamente. La mediana de la supervivencia global fue de 45.1 meses (IC del 95%: 22.2-63.8). En el análisis multivariado, la afectación cardíaca se asoció significativamente con una supervivencia global inferior (HR 3.27; IC del 95%: 1.23-8.73; p=0.018), ADQT-TAPH mostró una tendencia no significativa hacia una mejora en la supervivencia global (HR 0.25; IC 95%: 0.06-1.09; p=0.065). Conclusiones: En este estudio de pacientes colombianos con amiloidosis AL, la afectación renal fue más frecuente que la afectación cardíaca. La supervivencia global y la afectación multiorgánica fueron consistentes con datos de otras regiones del mundo. El análisis multivariado identificó la afectación cardíaca y ADQT-TAPH como posibles factores pronósticos.

AA Amyloidosis Secondary to Horton's Disease Complicated by Pulmonary Fibrosis: A Very Challenging Diagnosis and Therapy

AA amyloidosis is a classic and serious complication of many chronic inflammatory processes, whether of infectious, autoimmune, or neoplastic origin. It is frequently complicated by kidney damage, often in the form of a nephrotic syndrome. Giant cell arteritis is a common inflammatory arteritis in the elderly; however, it rarely causes AA amyloidosis. We report a rare case of Horton disease causing AA amyloidosis in an elderly patient with history of myopericarditis and repeated episodes of congestive heart failure. Patient was treated initially with dual therapy based on corticosteroids and anti TNF therapy (Tocilizumab) associated with heart failure therapy recommended by the European society of cardiology (ESC 2021 guidelines on Heart Failure). The initial outcome was favorable but later complicated by the involvement of the lungs; pulmonary fibrosis, responsible for repeated episodes of pleural effusion non controlled in spite of high dose of loop diuretics and repeated pleural punction. Patient died shortly after her second hospitalization due to respiratory insufficiency.

AL Amyloidosis with Polycythemia, Leucocytosis and Thrombocytosis : A Case Report

A young lady presented to us with clinical and biochemical evidence of Nephrotic Syndrome. Her laboratory investigations also revealed Erythrocytosis, Leucocytosis and Thrombocytosis. A renal biopsy revealed a diagnosis of Amyloidosis which was further characterized as AL amyloidosis with further investigations (kappa chain monoclonal gammopathy). She was started with appropriate therapy and she showed significant decline in her monoclonal Proteins on follow up. Her Erythrocytosis, Leucocytosis and Thrombocytosis also normalized with the decline in the levels of monoclonal light chains. We postulate a link between the monoclonal protein associated growth factors and inflammatory markers which were responsible for this unique association between AL Amyloidosis and tri-lineage hematopoietic cell proliferation.

Kidney Disease in Ankylosing Spondylitis: a case series and review of the literature / Doença Renal na Espondilite Anquilosante: uma série de casos e revisão da literatura

Abstract Background Kidney disease is a rare manifestation of ankylosing spondylitis (AS) and its pathological alterations remain poorly described. The aim of this study was to investigate the clinical presentation and pathological alterations on kidney biopsy of AS patients and review and discuss the current literature on the issue. Methods: We retrospectively studied the clinical presentation and kidney pathological alterations of 15 Caucasian AS patients submitted to kidney biopsy between October 1985 and March 2021. Results: Patients were predominantly male (66.7%) with median age at the time of kideney biopsy of 47 years [IQR 34 - 62]. Median serum creatinine at presentation was 1.3 mg/dL [IQR 0.9 - 3] and most patients also had either proteinuria (85.7%) and/or hematuria (42.8%). The most common indication for kidney biopsy was nephrotic syndrome (33.3%), followed by acute or rapidly progressive kidney injury (20%) and chronic kidney disease of unknown etiology (20%). Chronic interstitial nephritis (CIN) (n=3) and AA amyloidosis (n=3) were the most common diagnosis. Others included IgA nephropathy (IgAN) (n=2), focal segmental glomerulosclerosis (n=2), membranous nephropathy (n=1), and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN)(n=1). Conclusions: We present one of the largest series of biopsy-proven kidney disease in Caucasian AS patients. We found a lower prevalence of IgAN than previously reported in Asian cohorts. We found a higher prevalence of CIN and a lower prevalence of AA amyloidosis than that described in previous series of Caucasian patients. We also present the first case of AS-associated IC-MPGN.

Resumo Antecedentes: A doença renal é uma manifestação rara de espondilite anquilosante (EA) e as suas alterações patológicas permanecem pouco descritas. O objetivo deste estudo foi investigar a apresentação clínica e alterações patológicas na biópsia renal de doentes com EA bem como rever e discutir a literatura atual sobre o assunto. Métodos: Estudamos retrospectivamente a apresentação clínica e alterações patológicas renais de 15 doentes caucasianos com EA submetidos a biópsia renal entre Outubro de 1985 e Março de 2021. Resultados: Os doentes eram predominantemente homens (66,7%) com idade mediana no momento da biópsia de 47 anos [IIQ 34 - 62]. A creatinina sérica mediana na apresentação foi de 1,3 mg/dL [IIQ 0,9 - 3] e a maioria dos pacientes apresentava também proteinúria (85,7%) e/ou hematúria (42,8%). A indicação mais comum para biópsia renal foi a síndrome nefrótica (33,3%), seguida de lesão renal aguda ou rapidamente progressiva (20%) e doença renal crónica de etiologia desconhecida (20%). A Nefrite intersticial crónica (NIC) (n=3) e a amiloidose AA (n=3) foram os diagnósticos mais comuns. Outros incluíram nefropatia por IgA (NIgA) (n=2), glomeruloesclerose segmentar focal (n=2), nefropatia membranosa (n=1) e glomerulonefrite membranoproliferativa mediada por imunocomplexos (GNMP-IC) (n=1). Conclusões: Apresentamos uma das maiores séries de doenças renais comprovadas por biópsia em doentes caucasianos com EA. Encontramos uma prevalência de NIgA menor do que a relatada anteriormente em coortes asiáticas. Encontramos uma maior prevalência de NIC e uma prevalência menor de amiloidose AA do que a descrita em séries anteriores de pacientes caucasianos. Também apresentamos o primeiro caso de GNMP-IC associada à EA.

Brazilian consensus for diagnosis, management and treatment of hereditary transthyretin amyloidosis with peripheral neuropathy: second edition / Consenso brasileiro para o diagnóstico, manejo e tratamento da polineuropatia amiloidótica familiar associada à transtirretina: segunda edição

Abstract Hereditary transthyretin amyloidosis with peripheral neuropathy (ATTRv-PN) is an autosomal dominant inherited sensorimotor and autonomic polyneuropathy with over 130 pathogenic variants identified in the TTR gene. Hereditary transthyretin amyloidosis with peripheral neuropathy is a disabling, progressive and life-threatening genetic condition that leads to death in ~ 10 years if untreated. The prospects for ATTRv-PN have changed in the last decades, as it has become a treatable neuropathy. In addition to liver transplantation, initiated in 1990, there are now at least 3 drugs approved in many countries, including Brazil, and many more are being developed. The first Brazilian consensus on ATTRv-PN was held in the city of Fortaleza, Brazil, in June 2017. Given the new advances in the area over the last 5 years, the Peripheral Neuropathy Scientific Department of the Brazilian Academy of Neurology organized a second edition of the consensus. Each panelist was responsible for reviewing the literature and updating a section of the previous paper. Thereafter, the 18 panelists got together virtually after careful review of the draft, discussed each section of the text, and reached a consensus for the final version of the manuscript.

Resumo Polineuropatia amiloidótica familiar associada a transtirretina (ATTRv-PN) é uma polineuropatia sensitivo-motora e autonômica hereditária autossômica dominante com mais de 130 variantes patogênicas já identificadas no gene TTR. A ATTRv-PN é uma condição genética debilitante, progressiva e que ameaça a vida, levando à morte em ~ 10 anos se não for tratada. Nas últimas décadas, a ATTRv-PN se tornou uma neuropatia tratável. Além do transplante de fígado, iniciado em 1990, temos agora 3 medicamentos modificadores de doença aprovados em muitos países, incluindo o Brasil, e muitas outras medicações estão em desenvolvimento. O primeiro consenso brasileiro em ATTRv-PN foi realizado em Fortaleza em junho de 2017. Devido aos novos avanços nesta área nos últimos 5 anos, o Departamento Científico de Neuropatias Periféricas da Academia Brasileira de Neurologia organizou uma segunda edição do consenso. Cada panelista ficou responsável por rever a literatura e atualizar uma parte do manuscrito. Finalmente, os 18 panelistas se reuniram virtualmente após revisão da primeira versão, discutiram cada parte do artigo e chegaram a um consenso sobre a versão final do manuscrito.

Manejo ambulatorio de pacientes con amiloidosis cardiaca por cadenas livianas / Outpatient management of patients with cardiac light chain amyloidosis

Resumen La amiloidosis primaria o de cadenas livianas (AL) es la forma más común de amiloidosis y se caracteriza por presentar una población clonal de células plasmáticas que producen una cadena ligera monoclonal de tipo lambda o kappa. En algunos sujetos, dicha cadena se deposita en forma de amiloide en los órganos y tejidos, dando lugar a manifestaciones clínicas, como proteinuria o síndrome nefrótico, miocardiopatía restrictiva y hepatomegalia. Aunque se considera una enfermedad rara, datos recientes sugieren que la amiloidosis cardíaca se subestima como una causa de enfermedades o síndromes cardíacos comunes. En la amiloidosis AL, tanto la respuesta hematológica como la de los órganos después del tratamiento son importantes para mejorar el resultado clínico, especialmente, si mejora la función cardíaca que es uno de los aspectos clave en el pronóstico de la amiloidosis AL. Se presenta el caso y la revisión de un paciente de sexo femenino, de 67 años de edad, que en la pesquisa diagnóstica de anemia e insuficiencia cardiaca (IC) se concluye en el diagnóstico de mieloma múltiple y amiloidosis cardiaca (AC) por depósito de cadenas livianas.

Abstract Primary or light chain (AL) amyloidosis is the most common form of amyloidosis and is characterized by a clonal population of plasma cells that produce a monoclonal lambda or kappa-type light chain, which in some subjects this chain is deposited as amyloid in the organs and tissues, giving rise to clinical manifestations such as proteinuria or nephrotic syndrome, restrictive cardiomyopathy and hepatomegaly. Although considered a rare disease, recent data suggest cardiac amyloidosis is underestimated as cause of common heart diseases or syndromes. In AL amyloidosis, both the hematologic and organ response after treatment, are important to improve clinical outcome. Especially if it improves cardiac function is one of the key aspects in the prognosis of AL amyloidosis. We present the case and review of a 67-year-old female patient, who in the investigation diagnoses anemia and heart failure concludes in the diagnosis of multiple myeloma and cardiac amyloidosis due to light chain deposition.

Diagnosis and treatment progress of primary light-chain amyloidosis / 白血病·淋巴瘤

Primary light-chain (AL) amyloidosis is a rare and fatal plasma cell disease. In recent years, the treatment of AL amyloidosis has changed from the era of bortezomib to the era of daratumumab immunotherapy. However, for the treatment choice of advanced-staged patients, how to achieve organ responses at the early stage and how to monitor the disease are questions that need to be further explored. The 64th American Society of Hematology Annual Meeting in 2022 has reported advances in the diagnosis and treatment of AL amyloidosis, which are briefly reviewed in this article.

Progress in RNA-targeting and Gene Editing Therapies for Transthyretin Amyloidosis Cardiomyopathy / 罕见病研究

Transthyretin(TTR) protein is a tetramer protein, synthesized mainly by the liver. TTR can be misfolded and deposited as amyloid fibrilae and deposited in the myocardial interstroma leading to transthyroxin amyloidosis cardiomyopathy (ATTR-CM). ATTR-CM was included in China's First List of Rare Diseases. Therapeutic strategies for ATTR-CM include blocking TTR synthesis in the liver, stabilizing TTR tetramers and destroying TTR fibra. Small molecule drugs such as tafamidis and diflunisal offer new treatment options for patients. Chlorobenzolic acid became the first drug approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. Small interfering RNA(siRNA)patisiran and antisense oligonucleotide (ASO)inotersen block TTR expression in the liver and have been approved for the treatment of ATTR variant polyneuropathy (ATTRv-PN)and are in phase Ⅲ trials for the treatment of ATTR-CM. Other siRNA drugs, vutrisiran, and ASO, eplontersen, are being evaluated for clinical efficacy. This article reviews the development of RNA-targeted therapeutics and gene-editing drugs using CRISPR-Cas9.

The Interpretation and Update of the Diagnosis Pathway of Chinese Expert Consensus on the Diagnosis and Treatment of Transthyretin Cardiac Amyoidosis / 罕见病研究

Transthyretin cardiac amyloidosis (ATTR-CA) is caused by the deposition of transthyretin(TTR) in the myocardial interstitium. Its clinical manifestations are mainly heart failure and arrhythmia, leading to poor life quality and low survival rate. Diagnosis is often delayed or missed due to the lack of disease awareness, the non-specific clinical symptom presentation of the disease, and inadequacy of non-invasive diagnostic methods and medications in the past. The recent availability of effective treatments makes the early recognition and diagnosis especially critical, because treatment is likely more effective earlier in the disease course. Therefore, it is crucial to establish a diagnosis and treatment strategy to facilitate the rapid and accurate identification of the disease. Based on the advances in research and experiences gained ATTR-CA, our team has developed a consensus on diagnosis and treatment for the disease. In this article, we interpret the key points and present the update of diagnostic process, providing clinicians with an overview of key aspects of ATTR-CA in China.